Download Connective Tissue Disorders 61 Gene Panel

 Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier/Additional Provider
Submitting laboratory:
Sheffield RGC
1. Disorder/condition – approved name and symbol as published on the OMIM database (alternative
names will be listed on the UKGTN website)
If this submission is for a panel test please complete appendix 1 listing all of the conditions included
using approved OMIM name, symbol and OMIM number.
Connective Tissue Disorders - See appendix 1
2. OMIM number for disorder/condition
If a panel test – see 1. above
See appendix 1
3a. Disorder/condition – please provide, in laymen’s terms, a brief (2-5 sentences) description of
how the disorder(s) affect individuals and prognosis.
Connective tissue support organs and other parts of the body and can be described as the ‘biological
glue’ that gives tissues form and strength, as well as helping them function. Connective tissue disorders
often affect bones, muscles, and skin although organs such as the eyes, heart, lungs, kidneys, brain,
gastrointestinal tract, and blood vessels can also be involved.
Symptoms of a connective tissue disorder can include bone growth problems leading to deformity and
brittle bones, skin symptoms including poor wound healing, kidney disease, brain lesions, and weak
blood vessels that can easily rupture. These disorders can be severely disabling with pain and impaired
mobility. In severe cases connective tissue disorders are life threatening and can lead to death shortly
after birth.
3b. Disorder/condition – if required please expand on the description of the disorder provided in
answer to Q3a.
Alport syndrome is characterised by progress glomerulonephrities resulting in end stage renal failure. It
is associated with haematuria, characteristic eye signs and sensorineral deafness.
Collagen VI –related myopathies fall into the category of congenital muscular dystrophies and mainly
affect skeletal muscles. Individuals with these conditions may experience progressive muscle weakness
and develop contractures in the hands, wrists, elbows, and ankles. Mild respiratory muscle weakness is
also present.
Cutis Laxa is characterized by inelastic skin that is loose and sagging. Extremely wrinkled skin may be
evident on the face and neck giving a droopy appearance, and in the armpits and groin. Cutis Laxa can
also affect other organs, including the heart, joints, intestines, lungs and blood vessels including tearing
of arteries. Diverticula can also develop in the walls of organs such as the bladder and intestines.
Depending on which organs and tissues are affected, the signs and symptoms of cutis laxa can range
from mild to life-threatening.
Ehlers-Danlos Syndromes (EDS) are a group of disorders which share common features including
easy bruising, loose joints, skin that stretches easily and weakness of tissues. The outlook for individuals
with EDS depends on the type of EDS with which they have been diagnosed. Symptoms vary in severity,
even within one sub-type, and the frequency of complications changes on an individual basis. Some
individuals have negligible symptoms while others are severely restricted in their daily life. Vascular EDS
can be life threatening due to rupture of hollow organs.
Collagen IV -related disorders include: small-vessel brain disease of varying severity variably
associated with porencephaly, cerebral aneurysms, eye defects and systemic findings. Small-vessel
brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke,
ischemic stroke, and isolated migraine with aura. Familial Porencephaly is characterised by the presence
of fluid-filled cavities in the brain, caused by antenatal and/or perinatal parenchymal haemorrhage. Brain
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
imaging shows porencephalic cysts, varying degrees of leucoencephalopathy, cerebral micro
haemorrhage and lacunar infarct. The neurological symptoms vary in severity and age of onset. Typically
affected individuals present with infantile hemiparesis, seizures, mental retardation, dystonia, stroke and
migraine.
Familial Thoracic Aortic Aneursym (FTAA) syndromes exhibit phenotypic overlap and diagnosis can
be complicated by extensive phenotypic variability. They can be associated with a high morbidity and
mortality rate. The most common inherited form of syndromic aneurysms is Marfan syndrome that
presents with a wide range of clinical abnormalities including cardiovascular, skeletal, and ocular
abnormalities. Other syndromic conditions include Loeys-Dietz Syndrome, vascular Ehlers-Danlos
Syndrome , and Arterial tortuosity syndrome. Familial nonsyndromic aneurysms are characterized by
aneurysms without the presence of other clinical manifestations and typically follow an autosomal
dominant pattern of inheritance.
Osteogenesis Imperfecta (OI) is characterised by low bone mass and an increased tendency to
fracture, often with minimal or no apparent trauma. There is considerable variation in both severity and
age of onset, which ranges from death in the perinatal period to very mildly affected individuals with few
or no fractures. The clinical features of OI can include fractures, short stature with bone deformities,
hyperlaxity of joints and skin, and Wormian bones. Extraskeletal symptoms such as blue sclerae,
progressive adult hearing loss and dentinogenesis imperfecta may also be evident. Other important
features are bone pain and impaired mobility.
Stickler syndrome is a connective tissue disorder that can include ocular findings of high myopia,
cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial
underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild
spondyloepiphyseal dysplasia and/or precocious arthritis. Spinal abnormalities can include scoliosis or
kyphosis and platyspondyly.
4. Disorder/condition – mode of inheritance
If this submission is for a panel test, please complete the mode of inheritance for each condition in the
table in appendix 1.
See appendix 1
5. Gene – approved name(s) and symbol as published on HGNC database (alternative names will be listed
on the UKGTN website)
If this submission is for a panel test please complete appendix 1 listing all of the genes included using
approved HGNC name, symbol, number and OMIM number.
See appendix 1
6a. OMIM number(s) for gene(s)
If a panel test – see 5. above
See appendix 1
6b. HGNC number(s) for gene(s)
If a panel test – see 5. above
See appendix 1
7a. Gene – description(s)
If this submission is for a panel test, please provide total number of genes.
61 genes:
EDS -12
Bethlem Myopathy- 3
Alport- 3
Cutis Laxa- 7
Familial Porencephaly- 2
Familial Thoracic Aortic Aneurysms- 10
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
Osteogenesis Imperfecta All- 16
Stickler- 8
7b. Number of amplicons to provide this test (molecular) or type of test (cytogenetic)
(n/a for panel tests)
7c. GenU band that this test is assigned to for index case testing.
Band G 50-100 amplicons –Collagen IV - related disorders
Band H over 100 amplicons – Osteogenesis Imperfecta, Cutis Laxa, Ehlers Danlos Syndrome, Alports,
Collagen VI- related myopathy, Familial Thoracic Aortic Aneurysm, Stickler
8. Mutational spectrum for which you test including details of known common mutations
(n/a for panel tests) If this application is for a panel test to be used for different clinical phenotypes and/or
various sub panel tests – please contact the team for advice before completing a Gene Dossier
9a. Technical method(s) – please describe the test.
Clonal sequencing using the Illumina MiSeq platform.
SureSelect
 Shearing of genomic DNA using the Covaris E220 sonicator.
 End repair, A tailing and ligation of adaptors using SureSelectXT library system (Agilent
Technologies).
 Enrichment by SureSelect target enrichment (Agilent Technologies) using custom in house
designed probes. Samples have barcode tags added following target enrichment.
 Sequencing on the Illumina MiSeq using the MiSeq Reagent Kit v2 performing 2 x 150 bp end
paired reads.
Data Analysis
 Bases on the open source ‘Best Practices’ workflow by the Broad Institute (for additional
information, see http://www.broadinstitute.org/gatk/guide/best-practices).
 BWA alignment of reads to human genome build hg19.
 Generation of depth of coverage reports and checked using Alamut v 2.2 (Rev1) (Interactive
Biosoftware).
 A minimum threshold of 30-fold read depth is set for exonic sequences and intronic sequences
upto and including 5 bp from exon. A minimum threshold of 18-fold read depth is set for intronic
sequences from 6 bp to 25 bp from exon together with a visual check of all reads.
 Identification of variants using HaplotypeCaller. Annotation from dbSNP and COSMIC (currently
dbSNP138 and COSMIC v67 but updated with new releases)
 Variants filtered against in-house polymorphism lists and Best Practice Guidelines for the
evaluation of pathogenicity and the reporting of sequence variants in clinical molecular genetics
(Association for Clinical Genetic Science).
Post analysis
 Confirmation of all clinically significant sequence variants by Sanger sequencing.
 Filling of all gaps with low depth of coverage by Sanger sequencing.
 Creation of a diagnostic report combining clonal and Sanger sequence data.
9b. For panel tests, please specify the strategy for dealing with gaps in coverage.
Sanger sequencing is used to complete all gaps.
9c. Does the test include MLPA?
(For panel tests, please provide this information in appendix 1)
See appendix 1
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
9d. If NGS is used, does the lab adhere to the Association of Clinical Genetic Science Best
Practice Guidelines for NGS?
Yes
10. Is the assay to be provided by the lab or is it to be outsourced to another provider?
If to be outsourced, please provide the name of the laboratory and a copy of their ISO certificate
or their CPA number.
Assay is provided by the laboratory.
11. Validation process
Please explain how this test has been validated for use in your laboratory or submit your internal
validation documentation. If this submission is for a panel test, please provide a summary of evidence of:
i)
instrument and pipeline validation, and
ii)
panel verification for the test
Please submit as appendices to the Gene Dossier (these will be included in the published Gene Dossier
available on the website).
Please note that the preferred threshold for validation and verification is 95% sensitivity with 95%
Confidence Intervals.
Validation of the Miseq analysis pipeline was carried out using 31 patient samples in whom a number of
genes associated with glycogen storage disorders, connective tissue disorders, Fanconi anaemia and
hereditary cancer had been analysed by Sanger sequencing. All 341 variants previously detected by
Sanger sequencing were detected by the Miseq analysis pipeline. In addition, the Miseq analysis pipeline
did not detect any false positive variants.
The Connective Tissue Disorder (CTD) panel was validated by testing 7 patient samples for whom
previous Sanger sequencing analysis was available for 14 CTD genes. 164 variants previously identified
by Sanger sequencing were correctly identified. No false positive variants were reported by the Miseq
analysis pipeline.
The data obtained from the validation is above the preferred thresholds of 95% sensitivity with 95%
confidence intervals.
See attached validation documents 1 & 2.
12a. Are you providing this test already?
Yes
12b(i). If yes, how many reports have you produced?
34
12b(ii). Number of reports mutation positive?
14
12b(iii). Number of reports mutation negative?
20
12b(iv). Please provide the time period in which these reports have been produced and whether in
a research or a full clinical diagnostic setting.
The service was moved from sanger sequencing to NGS on 4th November 2013. Thirty four reports have
been issued via this pipeline.
Testing for OI was established in 2002 and for EDS was introduced in 2009. Further connective tissue
disorders have been developed over the last 5 years. More than 1000 reports have been issued for these
conditions.
All reports have been issued in a clinical diagnostic setting.
13a. Is there specialised local clinical/research expertise for this disorder?
Yes
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
13b. If yes, please provide details
Prof ACM Ong
Professor of Renal Medicine
Head, Academic Unit of Nephrology
University of Sheffield
Dr JA Cook
Consultant Clinical Genetics
Renal Genetics Clinic
Department of Clinical Genetics
Sheffield Children's NHS Foundation Trust
Dr Glenda J Sobey
Consultant Dermatologist
EDS Specialist Clinic
Dept of Clinical Genetics
Sheffield Children's NHS Foundation Trust
Dr Chris Rittey
Consultant Paediatric Neurologist
Sheffield Children's NHS Foundation Trust
Dr Diana Johnson
Consultant Clinical Genetics
Department of Clinical Genetics
Sheffield Children's NHS Foundation Trust
Dr Meena Balasubramanian
Consultant Clinical Geneticist
Lead Consultant, OI-Genetics Service, NCG-OI Service
Honorary Senior Clinical Lecturer
University of Sheffield
Sheffield Clinical Genetics Service
Sheffield Children's NHS Foundation Trust
Prof N Bishop
Professor of Paediatric Bone Disease
Heads of Metabolic Bone Disease
Sheffield Children's NHS Foundation Trust
14. Based on experience what will be the national (UK wide) activity, per annum, for:
Index cases: 965
Family members where mutation is known: 345
15. If your laboratory does not have capacity to provide the full national need please suggest how
the national requirement may be met.
For example, are you aware of any other labs (UKGTN members or otherwise) offering this test to NHS patients on a local area
basis only? This question has been included in order to gauge if there could be any issues in equity of access for NHS patients.
If you are unable to answer this question please write “unknown”.
N/A
16. If using this form as an Additional Provider application, please explain why you wish to
provide this test as it is already available from another provider.
N/A
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
EPIDEMIOLOGY
17a. Estimated prevalence of conditions in the general UK population
Prevalence is total number of persons with the condition(s) in a defined population at a specific time.
Please identify the information on which this is based.
For panel tests, please provide estimates for the conditions grouped by phenotypes being tested.
Alport syndrome: 1/50,000 (http://ghr.nlm.nih.gov/condition/alport-syndrome)
Collagen VI related Myopathy: Prevalence is estimated at 0.77:100,000 in Bethlem myopathy and
0.13:100,000 in Ullrich CMD (http://www.ncbi.nlm.nih.gov/books/NBK1503)
Cutis Laxa: Prevalence for all types of cutis laxa is approximately 1:1,000,000
(http://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=209)
EDS: Classical EDS: 1/20,000 (Byers PH Disorders of collagen biosynthesis and structure Scriver,
Beaudet, Sly, Valle eds The metabolic and molecular basis of inherited disease. 2 ed Edinburgh, UK
Churchill Livingstone; 2001: 1065-81).
Vascular EDS: 1/50,000-1/200,000 (Byers PH Gene Reviews) Many families with vascular EDS are only
identified after a severe complication or death, therefore the prevalence may be higher.
Kyphoscoliotic EDS: 1/100,000 (Yeowell NH, Steinmann B Gene Reviews) Combined 1/5000 (Genetics
Home Reference- http://ghr.nlm.nih.gov/condition/ehlers-danlos-syndrome).
Collagen IV-related disorders: Unknown as there is no data available
(http://ghr.nlm.nih.gov/condition/familial-porencephaly) and only 17 families have been described
(http://www.ncbi.nlm.nih.gov/books/NBK7046/)
FTAA:
Loeys-Dietz: Not known
Marfan syndrome 1/5,000 (Orphanet- Prevalence of rare diseaseshttp://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetical_list.pdf)
TAAD 1/5,000-10,000
(http://ukgtn.nhs.uk/fileadmin/uploads/ukgtn/Documents/Resources/Library/Reports_Guidelines/UKGTN
%20Workshop%20%20Marfan%20report%20%202012.pdf)
OI: 1/15-20,000 (Forlino and Marini (2000) Mol Genet Metab 71: 225-32)
Stickler: No studies to determine the prevalence of Stickler syndrome have been undertaken
(http://www.ncbi.nlm.nih.gov/books/NBK1302)
17b. Estimated annual incidence of conditions in the general UK population
Incidence is total number of new cases in a year in a defined population.
Please identify the information on which this is based.
For panel tests, please provide for groups of conditions.
Alport: Not known
Collagen VI related myopathy: There is no data available for specific incidence in the UK
Cutis Laxa: Incidence for all types of cutis laxa is approximately 1:4,000,000
(http://www.ncbi.nlm.nih.gov/books/NBK5201)
EDS: Individual incidence not known but combined EDS has an incidence of 1/5000 (Whitelaw SE;
Ehlers-Danlos syndrome, classical type: case management. Dermatol Nurs. 2004 Oct;16(5):433-6, 449.)
Collagen IV related disorders: Unknown as there is no data available
FTAA:
Loeys-Dietz: Not known
Marfan Syndrome - 1/3,300
(http://ukgtn.nhs.uk/fileadmin/uploads/ukgtn/Documents/Resources/Library/Reports_Guidelines/UKGTN
%20Workshop%20%20Marfan%20report%20%202012.pdf)
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
TAAD- 1/10,000
(http://ukgtn.nhs.uk/fileadmin/uploads/ukgtn/Documents/Resources/Library/Reports_Guidelines/UKGTN
%20Workshop%20%20Marfan%20report%20%202012.pdf)
OI:
Types I, III, IV - 1/15-20,000 (Forlino and Marini (2000) Mol Genet Metab 71: 225-32)
Type II – 1/50,000-60,000 (Baldridge et al (2008) Hum Mut 29(12): 1435-1442)
Stickler: Approximate incidence of Stickler syndrome among newborns can be estimated from data
regarding the incidence of Robin sequence in newborns (1:10,000-1:14,000) and the percent of these
newborns who subsequently develop signs or symptoms of Stickler syndrome (35%). These data
suggest that the incidence of Stickler syndrome among neonates is approximately 1:7,500-1:9,000
[Printzlau & Andersen 2004]. (http://www.ncbi.nlm.nih.gov/books/NBK1302)
18. Estimated gene frequency (Carrier frequency or allele frequency)
Please identify the information on which this is based.
n/a for panel tests.
19. Estimated penetrance of the condition. Please identify the information on which this is based
n/a for panel tests
20. Estimated prevalence of conditions in the population of people that will be tested.
n/a for panel tests.
INTENDED USE
(Please use the questions in Annex A to inform your answers)
21. Please tick either yes or no for each clinical purpose listed.
Panel Tests: a panel test would not be used for pre symptomatic testing, carrier testing and pre natal
testing as the familial mutation would already be known in this case and the full panel would not be
required.
Diagnosis
Yes
No
Treatment
Yes
No
Prognosis & management
Yes
No
(n/a for Panel Tests)
Yes
No
Carrier testing for family members (n/a for Panel Tests)
Yes
No
Prenatal testing
Yes
No
Presymptomatic testing
(n/a for Panel Tests)
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
TEST CHARACTERISTICS
22. Analytical sensitivity and specificity
This should be based on your own laboratory data for the specific test being applied for or the analytical sensitivity and
specificity of the method/technique to be used in the case of a test yet to be set up.
Please note that the preferred threshold for validation and verification is 95% sensitivity with 95%
Confidence Intervals.
Validation data for the Miseq analysis pipeline shows that the test sensitivity is >99% and test specificity
is >99%.
23. Clinical sensitivity and specificity of test in target population
The clinical sensitivity of a test is the probability of a positive test result when condition is known to be present; the clinical
specificity is the probability of a negative test result when disorder is known to be absent. The denominator in this case is the
number with the disorder (for sensitivity) or the number without condition (for specificity).
Please provide the best estimate. UKGTN will request actual data after two years service.
Clinical Sensitivity
Alport- (http://ghr.nlm.nih.gov/condition/alport-syndrome)
15% will have mutations in COL4A3 or COL4A4
80% will have mutations in COL4A5
Collagen VI related Myopathy- (http://www.ncbi.nlm.nih.gov/books/NBK1503)
COL6A1 = 38%
COL6A2 = 44%
COL6A3 = 18%
Cutis Laxa
50-92%
It is difficult to estimate the clinical sensitivity in patients with ADCL, as little literature is available. In
ARCL, investigation of 12 pedigrees found mutations in 11 probands giving a sensitivity of 92%. We
would expect the clinical sensitivity of this panel to be lower than this.
EDS
Classical EDS type 50–90% (COL5A1 and COL5A2 gene),which is genetically heterogeneous with
additional, still unknown gene loci (Malfait F, Wenstrup RJ, De Paepe A (2010) Genet Med; 12: 597–
605; Symoens S et al (2012) Hum Mutat 33: 1485-1493.
95% for Vascular EDS (COL3A1 gene), (Germain DP (2007): Ehlers-Danlos syndrome type IV.
Orphanet J Rare Dis 19: 2–32), arthrocholasic EDS (COL1A1 and COL1A2 gene, respectively) and
kyphoscoliotic EDS (PLOD1 gene) (Rohrbach M et al (2011) Orphanet J Rare Dis 23: 6–46.)
Sensitivity is not known in the recessively inherited clinical entities including Brittle Cornea syndrome 1
and 2 (ZNF469 and PRDM5 gene), D4ST1-deficient EDS (CHST14 gene), FKBP14-deficient EDS,
dermatosparactic type (ADAMTS2 gene), EDS progeroid form (B4GALT7 gene) and EDS
spondylocheiro dysplastic form (SLC39A13 gene). (Burkitt Wright EM et al, (2011) Am J Hum Genet 88:
767–777; Malfait F et al, (2010) Hum Mutat 31: 1233–1239; Baumann M et al, (2012) Am J Hum Genet
90: 201–216; Colige A et al, (2004) J Invest Dermatol 123: 656–663).
Collagen IV related disorders
Porencephaly has a variable phenotype and age of onset and as such this affects the clinical sensitivity.
Not all mutation carriers have infantile porencephaly and hemiparesis, but have migraine or cerebral
haemorrhage in adulthood. Combining both genes will increase the sensitivity
FTAA
Loeys-Dietz:The clinical sensitivity has been reported as 95% Loeys at al (2006) N Eng J Med 355(8):
788-98
Marfan syndrome : The clinical sensitivity has been reported as 90% in Marfan syndrome (Loeys et al
(2004) Hum Mutat 24:140-6) with mutations primarily in FBN1 but up to 21% of mutations are found in
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
TGFBR2 (Saiki et al (2006) Am J Med Genet A 140(16):1719-25.; Mizuguchi et al (2004) Nat Genet
36(8):855-60)
TAAD: ACATA2- 14% (Guo et al (2007) Nat Gen 36(12):1448-93; TGFBR2- 5% (Matyas et al (2006)
Hum Mutat. 27(8):760-9 ; FBN1- unkown; TGFBR1- unknown
Vasucular EDS 95% (see above)
OI
Dominant OI is approximately 85-90% and recessive OI is approximately 10-15%
(http://www.oif.org/site/PageServer?pagename=fastfacts)
Stickler- (http://www.ncbi.nlm.nih.gov/books/NBK1302)
COL2A1 = 80-90% mutations
COL11A1 = 10-20% mutations
CO11A2, COL9A1, COL9A2, COL9A3 = rare
24. Clinical validity (positive and negative predictive value in the target population)
The clinical validity of a genetic test is a measure of how well the test predicts the presence or absence of the phenotype,
clinical condition or predisposition. It is measured by its positive predictive value (the probability of getting the condition given
a positive test) and negative predictive value (the probability of not getting the condition given a negative test).
Not currently requested for panel tests
25. Testing pathway for tests where more than one gene is to be tested sequentially
Please include your testing strategy if more than one gene will be tested and data on the expected proportions of positive
results for each part of the process. Please illustrate this with a flow diagram. This will be added to the published Testing
Criteria.
n/a for panel tests
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
CLINICAL UTILITY
26. How will the test change the management of the patient and/or alter clinical outcome?
Please describe associated benefits for patients and family members. If there are any cost
savings AFTER the diagnosis, please detail them here.
General
Accurate diagnosis allowing appropriate, effective treatment and improved surveillance. Identification
and counselling of at risk relatives. First trimester prenatal diagnosis made possible.
The availability of a panel test will result in a significant cost saving due to the removal of the need for
sequential gene testing, biochemistry and possible need for skin/kidney/muscle/bone biopsy and will
lead to a much quicker diagnosis for the patient.
Alport
The establishment of mode of inheritance is important in assessing the potential clinical outcome and
therefore informs treatment and management strategies.
In addition, testing of family members becomes available where either a molecular diagnosis is required
for their clinical management/reproductive decisions or they wish to act as a living kidney donor.
Collagen VI - related myopathy
Collagen type VI-related disorders represent a continuum of overlapping phenotypes with Bethlem
myopathy at the mild end, Ullrich congenital muscular dystrophy (CMD) at the severe end, and two
rare, less well-defined disorders – autosomal dominant limb-girdle muscular dystrophy and autosomal
recessive myosclerosis myopathy – in between. Although Bethlem myopathy and Ullrich CMD were
defined long before their molecular basis was known, they remain useful for clarification of prognosis
and management.
Bethlem myopathy, characterized by the combination of proximal muscle weakness and variable
contractures, affects most frequently the long finger flexors, elbows, and ankles. Onset may be prenatal
(characterized by decreased fetal movements), neonatal (hypotonia or torticollis), in early childhood
(delayed motor milestones, muscle weakness, and contractures), or in adulthood (proximal weakness
and Achilles tendon or long finger flexor contractures). Because of slow progression, more than two
thirds of affected individuals over age 50 years rely on supportive means for outdoor mobility.
Respiratory involvement is rare and appears to be related to more severe muscle weakness in later life.
Ullrich CMD is characterized by congenital weakness and hypotonia, proximal joint contractures, and
striking hyperlaxity of distal joints. Some affected children acquire the ability to walk independently;
however, progression of the disease often results in later loss of ambulation. Early and severe
respiratory involvement may require ventilatory support in the first or second decade of life.
Genotyping clarifies the inheritance pattern, provides some prognostic information and allows prenatal
testing. Provides information on whether cardiac screening is required.
Cutis Laxa
Cutis laxa has several different forms. The effects of this condition are not only on the skin causing
loose folds of wrinkled skin at an early stage, but can also affect the heart, blood vessels, joints,
intestines and lungs. The bladder can also be affected. The signs and symptoms of cutis laxa can vary
from mild to life threatening.
Cutis laxa can be caused by mutations in a variety of genes. By knowing which gene is affected,
patients can be appropriately managed according to the organ systems affected in that type.
Inheritance in the family can also be accurately determined as this varies between the different types of
cutis laxa. Presymptomatic testing to identify individuals at risk for cardiovascular and pulmonary
disease is made available.
EDS
EDS describes a group of separate conditions with different genetics. These conditions need to be
differentiated so that accurate diagnosis of subtype can lead to appropriate management. Some
subtypes have a risk of sudden death and these patients need appropriate monitoring. The confirmation
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
of a subtype with no life threatening features means that further investigations and particularly
expensive cardiovascular monitoring are not required.
COL4A1-related disorders
These include: small-vessel brain disease of varying severity variably associated with porencephaly,
cerebral aneurysms, eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and
systemic findings (kidney involvement, muscle cramps, Raynaud phenomenon, and cardiac arrhythmia)
Small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent
hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly(fluid-filled cavities
in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and
intellectual disability; however, on occasion it can be an incidental finding. Hereditary Angiopathy with
Nephropathy, Aneurysms, and muscle Cramps (HANAC) syndrome usually associates asymptomatic
small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings
involving the kidney, muscle, and small vessels of the eye.
Porencephalic cysts may occur after antenatal or neonatal parenchymal hemorrhagic infarction in the
context of neonatal alloimmune thrombocytopenia, or a coagulopathy like von Willebrand disease,
factor V or factor X deficiency, maternal warfarin use, or thrombophilia (most often heterozygosity for
factor V Leiden mutation).
It is important to differentiate familial porencephaly from these alternate causes as it affects pregnancy
management and information given to families with regard to recurrence risk
Cesarean delivery of fetuses at risk for a COL4A1-related disorder to prevent brain vascular injury
resulting from birth trauma. Avoid anticoagulant use.
FTAA
Diagnosis of these conditions will allow for prompt appropriate and potentially life-saving treatment.
Non-invasive screening for sites of arterial aneurysm may reduce morbidity and mortality. Affected
individuals should be instructed to seek immediate medical attention for sudden unexplained pain. For
some patients elective surgery may be discouraged due to increased tissue fragility resulting in a high
risk of surgical complications. Pregnancy in women with these conditions can be associated with
increased risk of death from peripartum arterial rupture or uterine rupture and should be managed in a
high risk obstetric program.
Osteogenesis Imperfecta
Mutation analysis will confirm diagnosis of OI, inform the mode of inheritance and allow assessment of
recurrence risk. In the event that an individual with a mild/moderate dominant mutation wishes to
consider PND then recurrence risk is 50%. Mutation analysis in the affected individual would be
required and allow reduction in late terminations or birth of affected children. Late prenatal testing is
sometimes requested for delivery management. Molecular diagnosis also allows rapid predictive
analysis of the newborn (2 weeks) and reduced parental anxiety.
Severe OI can result from either a de novo dominant mutation where the risk of recurrence is
associated with germline or somatic mosaicism in either parent, or recessive OI where there is a 25%
recurrence risk. Though gonadal mosaicism cannot be tested for directly it is likely that absence of
identifiable somatic mosaicism results in a reduced risk to the couple. Without mutation analysis each
subsequent pregnancy may require ultrasound scans from 14-16wks onwards and in the event of an
affected fetus, a late termination by induction of labour. There is also significant parental anxiety.
OI is one of the rare genetic conditions where there is treatment available in the form of
bisphosphonates which has dramatically changed the clinical outcome of patients with this condition.
However, not being able to determine the genotype is difficult when trying to predict treatment
outcomes, especially for patients with milder form of the condition. As a Clinician, it is important to
ascertain the genotype so as to predict outcome, management implications and provide prognostic and
recurrence risk information to patient and/or families.
Stickler
Testing with provide Individuals with a definitive diagnosis and this allows appropriate follow up which
should include annual examination by a vitreoretinal specialist+/- prophylactic surgery; audiologic
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
evaluations every six months through age five years, then annually thereafter. Life style advice to
reduce risk of complications. It will provide information on recurrence risk in families
27. If this test was not available, what would be the consequences for patients and family
members?
General : Can be difficult to assess potential clinical outcome and therefore develop appropriated
monitoring and/or management plans, leading to poorer outcome. Lack of accurate identification of the
mode of inheritance would not allow appropriate counselling of at risk family members and carrier,
presymptomatic and prenatal testing is not possible.
Alports syndrome: For this condition the inability to investigate carrier status may preclude family
members from being live kidney donors.
Collagen VI-related disorders: Patients with myopathy would not be differentiated into subtype.
Unnecessary cardiac screening might occur. Prenatal diagnosis would then not be available. It would
not be possible to determine if recurrence risk was < 1/200 or ¼ for simplex cases.
Cutis Laxa Cutis laxa patients need to have the genetic basis of their condition determined otherwise
under or over -management would be likely. Prenatal diagnosis would then not be available which is
particularly important in the life threatening types.
EDS: These patients would not be differentiated into subtype meaning that under or over -management
would be likely. Prenatal diagnosis would then not be available which is particularly important in the life
threatening types.
Collagen IV-related disorders: Pregnancies might not be managed correctly and it would not be
possible to give accurate information to families about recurrence. Prenatal testing would not be
possible.
FTAA: Appropriate organisation of elective surgery may not be possible without accurate diagnosis.
The need for referral to high risk obstetric program may not be identified. Prompt and appropriate
medical management may not be available.
OI: Testing in OI to determine the genetic cause is important to provide information regarding
recurrence risks, option of prenatal diagnosis especially with various patterns of inheritance that have
been described. It alters clinical management in particular, decisions regarding therapeutic options
especially in children with milder forms of bone fragility.
Stickler syndrome caused by mutations in COL2A1, COL11A1, or COL11A2 is inherited in
an autosomal dominant manner; Stickler syndrome caused by mutations in COL9A1 or COL9A2 is
inherited
in
an autosomal
recessive manner.
In
families
with
autosomal
dominant
inheritance, affected individuals have a 50% chance of passing on the mutation to each offspring. In
families with autosomal recessive inheritance, each sib of an affected individual has a 25% chance of
being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of
being unaffected and not a carrier. Prenatal testing is possible in pregnancies at increased risk if
the disease-causing mutation(s) in the family are known. In simplex cases if no mutation is identified it
is not possible to give families accurate information with regards to recurrence risk, the possibility of
severe eye phenotype or offer prenatal tests.
28. Is there an alternative means of diagnosis or prediction that does not involve molecular
diagnosis? If so (and in particular if there is a biochemical test), please state the added advantage of
the molecular test.
Alport Syndrome: Renal biopsy (minimum cost £917), immunohistochemistry (£35 per antibody) of
skin biopsy, ophthalmic assessment.
Collagen VI related myopathy: Clinical assessment and muscle biopsy (£292) may suggest Bethlem
vs Ullrich however there is considerable overlap in phenotype and only molecular genetic testing is
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
definitive.
Cutis Laxa: There is no other accurate measure. Skin biopsy only demonstrates the reduction /
absence of elastin but can not confirm the exact diagnosis or the affects on other organ systems. Only
molecular diagnosis will allow prenatal diagnosis.
EDS: There is no other accurate measure for EDS. Collagen species analysis can be used in Vascular
EDS but not accurately in other types. Electron microscopy of skin biopsy can be undertaken but
findings can be non specific and are not considered to be diagnostic. These methods would not allow
prenatal diagnosis
Collagen IV-related disorders: It is not possible to clinically distinguish familial porencephaly from the
adult onset form of this condition which is autosomal dominant is very difficult to distinguish clinically
from CARASIL which is autosomal recessive.
FTAA: The only other method of diagnosis is by clinical evaluation using diagnostic criteria such as
Ghent and Villfranche. However these conditons can have variable and overlapping clinical
OI : Bone biopsy, which is highly invasive and needs to be performed under anaesthetic, does not
provide adequate information for diagnosis and gives broad information on bone turn-over. Skeletal
survey and DXA scans are used to type OI but this does not provide any information on the likely
genetic cause. Urine NTx is used as a biochemical marker but again not specific enough and is more
useful in monitoring response to treatment rather than being useful from a diagnostic point of view.
Collagen analysis from skin biopsy has reduced positive and negative predictive value compared to
genetic analysis due to subjective interpretation and lower sensitivity of assay. Electron microscopy of
skin biopsy can be undertaken but findings can be non specific and are not considered to be diagnostic
in isolation.
Stickler: A small proportion of individuals with Stickler can be diagnosed on the basis of their eye
phenotype. However there are only a very limited number of Ophthalmologists able to do this.
29a. What unexpected findings could this test show? For example, lung cancer susceptibility
when testing for congenital cataract because ERCC6 gene (primarily associated with lung
cancer) is included in a panel test for congenital cataract.
The bioinformatics pipeline has been developed to enable the specific sub-panel relevant to the
phenotype being investigated to be analysed. It is not therefore anticipated that there will be any
unexpected findings.
29b. Please list any genes where the main phenotype associated with that gene is unrelated to
the phenotype being tested by the panel.
N/A
30. If testing highlights a condition that is very different from that being tested for, please
outline your strategy for dealing with this situation.
N/A
31. If a panel test, is this replacing an existing panel/multi gene test and/or other tests currently
carried out through UKGTN using Sanger sequencing? If so, please provide details below.
Sequential Sanger sequencing of some of the genes associated with Osteogenesis Imperfecta, Ehlers
Danlos Syndrome, Alport Syndrome, Collagen VI-related myopathy, collagen IV related disorders and
Stickler Syndrome are available.
The Familial Thoracic Aortic Aneurysm panel incorporates Marfan syndrome, Loeys Dietz, vascular
Ehlers Danlos Syndrome and familial Thoracic Aortic Aneurysm with Dissection. These are listed as
single disorders on UKGTN.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
32. Please describe any specific ethical, legal or social issues with this particular test.
IS IT A REASONABLE COST TO THE PUBLIC?
33. In order to establish the potential costs/savings that could be realised in the diagnostic care
pathway, please list the tests/procedures that would be required in the index case to make a
diagnosis if this genetic test was not available.
Costs and type of imaging procedures
Costs and types of laboratory pathology tests
(other than molecular/cyto genetic test proposed in this Gene
Dossier)
Costs and types of physiological tests (e.g. ECG)
Cost and types of other investigations/procedures (e.g. biopsy)
Total cost of tests/procedures no longer required
(please write n/a if the genetic test does not replace any other
tests procedures in the diagnostic care pathway)
Type of test
Cost (£)
Electron
microscopy
£350
Fibroblast culture
£252.50
Collagen species
analysis.
£420
Sequential
testing
£1500
Skin biopsy
gene
£143
£2665.50
34. Based on the expected annual activity of index cases (Q14), please calculate the estimated
annual savings/investments based on information provided in Q33.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
Number of index cases expected annually
Cost to provide tests for index cases if the
genetic test in this Gene Dossier was not
available (see Q33)
Total annual costs pre genetic test
Total annual costs to provide genetic test
Additional savings for 100% positive rate for
index cases
Percentage of index cases estimated to be
negative
Number of index cases estimated to be negative
Costs to provide additional tests for index cases
testing negative
Total costs for tests for index patient activity
(a) 965
(b) £2665.50
(a) x (b) = (c) £2,572,207
(a) x cost of genetic testing for index case = (d)
£892,625
(d) – (c) = (e) -£1,679,582
(f) 50
(f) x number of index cases = (g) 482
(g) x (b) = (h) 482X1165= £561,771
Total costs for family members
(e) + (h) = (i)
-£1,679,528+£561,771 =£-1,117,757
Costs for family member test x number of family
members expected to test in a year
345X155=£53,475
If there is a genetic test already available and
some of the family testing is already being
provided, please advise the cost of the family
testing already available
Cost for family member testing already available
x estimated number of tests for family members
already provided (k)
345X155=£53,475
Total costs for family members minus any family
member testing costs already provided
Additional savings for all activity expected in a
year
HSS Complex/Atypical EDS Service: testing for
~150 probands (£138,750).
HSS Complex/Atypical OI : testing for 15
probands only (£13,875)
(j) – (k) = (l) 0
(i) + (j) or (i) + (l) = £1,117,757
35. REAL LIFE CASE STUDY
Please provide a case study that illustrates the benefits of this test
13-year female patient, 3rd child of healthy, non-consanguineous parents with no significant family
history. Antenatally, there was no concerns identified and she was born at term. Following birth, she
sustained several rib fractures prompting a diagnosis of OI. Skeletal survey pointed towards a
diagnosis of type 3 OI. Genetic testing failed to identify a causative mutation in COL1A1 or COL1A2.
She was followed up by the Metabolic Bone team in Sheffield and subsequently in Manchester for
several years and has been on treatment with Pamidronate.
This patient was seen in the OI-Genetics clinic under the auspices of the Severe/Complex OI service in
Sheffield. Testing through the Next generation CTD panel identified a homozygous mutation in exon 1
CRTAP, thus confirming the diagnosis of OI but also providing accurate recurrence risks for this family
who have older children of a child-bearing age. It also provided prognostic information for this patient
and her family.
This real life case study illustrates the clinical utility and advantages of accessing the OI panel test as
part of the specialised services in Sheffield.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
TESTING CRITERIA
36. Please only complete this question if there is previously approved Testing Criteria.
Please contact the UKGTN office if you are unsure whether testing criteria is available.
36a. Do you agree with the previously approved Testing Criteria? No
36b. If you do not agree, please provide revise Testing Criteria on the Testing Criteria form and
explain below the reasons for the changes.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Collagen VI Related Myopathy 3 Gene Panel
Approved name and symbol of disorder/condition(s):
Bethlem Myopathy
Ullrich Congenital Muscular Dystrophy
OMIM number(s):
158810
254090
Approved name and symbol of gene(s):
collagen, type VI, alpha 1; COL6A1
collagen, type VI, alpha 2; COL6A2
collagen, type VI, alpha 3; COL6A3
OMIM number(s):
120220
120240
120250
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers
to you.
Consultant Clinical Genetics
Consultant Neurologist
Consultant Paediatrician
Minimum criteria required for testing to be appropriate as stated in the Gene
Dossier:
Criteria
Tick if this patient
meets criteria
Myopathy phenotype with typical concentric signal abnormality on
muscle MRI OR
Reduced/absent collagen VI in muscle, OR
Abnormal COL6 in fibroblast culture
Additional Information:
At risk family members where familial mutation is known do not require a full panel test
but should be offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified
types of referrer and you still feel that testing should be performed please contact
the laboratory to discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Alport Syndrome 3 Gene Panel
Approved name and symbol of disorder/condition(s):
Alport Syndrome, Autosomal Dominant
Alport Syndrome, Autosomal Recessive
Alport Syndrome, X-Linked; ATS
Benign Familial Haematuria
Approved name and symbol of gene(s):
collagen, type IV, alpha 3 (Goodpasture antigen); COL4A3
collagen, type IV, alpha 4; COL4A4
collagen, type IV, alpha 5; COL4A5
OMIM number(s):
104200
203780
301050
141200
OMIM number(s):
120070
120131
303630
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers
to you.
Consultant Clinical Geneticist
Consultant Nephrologist
Consultant Ophthalmologist
Consultant Paediatrician
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
CriteriaTick if this patient
At least 2 of the following criteria must be met by the proband:
meets criteria
Positive family history of haematuria or chronic renal failure
Electron microscope evidence of Alport syndrome on renal biopsy
High tone sensorineural deafness
Characteristic ophthalmic signs (perimacular dots and flecks or anterior
lenticous)
OR
Immunochemical evidence of loss of COL4A3 OR COL4A4 staining on a
skin biopsy
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should
be offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact the laboratory to
discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Stickler 8 Gene Panel
Approved name and symbol of disorder/condition(s):
OMIM number(s):
See appendix 1
See appendix 1
Approved name and symbol of gene(s):
OMIM number(s):
See appendix 1
See appendix 1
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticist
Consultant Ophthalmologist
Consultant Orthopaedist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
Skeletal abnormalities affecting joints e.g. hypermobility, joint pain,
scoliosis, hyphosis, osteoarthritis etc AND
Cleft palate (or family history of cleft palate) AND
Sensori-neural hearing loss AND
Normal vitreous phenotype
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should
be offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact the laboratory to
discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Cutis Laxa 7 Gene Panel
Approved name and symbol of disorder/condition(s):
Cutis Laxa:
Occipital Horn Syndrome;
Supravalvular Aortic Stenosis;
Approved name and symbol of gene(s):
See appendix 1
OMIM number(s):
614434
304150
185500
OMIM number(s):
See appendix 1
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticist
Consultant Paediatrician
Consultant Dermatologist
Consultant Cardiologist
Consultant in Respiratory Medicine
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
Loose/sagging/inelastic skin AND
Emphysema OR
Supravalvular Aortic Stenosis OR
Radiological features of Occipital horn syndrome
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should
be offered analysis of the known mutation.
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact the laboratory to
discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Osteogenesis Imperfecta 16 Gene Panel
Approved name and symbol of disorder/condition(s):
See appendix 1
OMIM number(s):
See appendix 1
Approved name and symbol of gene(s):
See appendix 1
OMIM number(s):
See appendix 1
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to you.
Consultant Clinical Geneticist
Consultant Paediatrician
Consultant in Bone Metabolism/Endocrinologist
Consultant Neonatologist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient meets
criteria
Multiple fractures of long bones without significant trauma AND at
least two of the following:
 Wormian bones
 Blue/grey sclera
 Hearing loss
 Ribs, broad and beaded, thin and irregular
 Short stature
 Dentinogenesis imperfecta
 Triangular face and narrow thorax
 Round facies and short barrel-shaped chest
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should
be offered analysis of the known mutation.
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact the laboratory to
discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Thoracic Aortic Aneurysms 10 Gene Panel
Approved name and symbol of disorder/condition(s):
See appendix 1
OMIM number(s):
See appendix 1
Approved name and symbol of gene(s):
See appendix 1
OMIM number(s):
See appendix 1
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Consultant Clinical Geneticist
Tick if this refers to you.
Consultant Cardiologist
Consultant Ophthalmologist
Consultant Paediatrician
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient meets
criteria
A patient should have at least one of the three following features:
Dilated aortic root OR
Tortuosity or aneurysm of other arteries OR
Intestinal/uterine fragility or rupture
AND
Ectopia lentis OR
Marfanoid habitus OR
Excessive bleeding OR
Characteristic facial appearance for one of these conditions including
a decrease in subcutaneous adipose tissue, particularly face and
limbs OR
Positive family history, sudden death in a close relative
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should be
offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Ehlers-Danlos 12 gene panel
Approved name and symbol of disorder/condition(s):
See appendix 1
OMIM number(s):
See appendix 1
Approved name and symbol of gene(s):
See appendix 1
OMIM number(s):
See appendix 1
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticist
Consultant Paediatrician
Consultant Neurologist
Consultant Dermatologist
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
Skin hyperextensibility AND Joint hypermobility and laxity AND one of the
following:
Widening atrophic scars (tissue fragility)
Easy bruising
Muscle hypotonia
Scoliosis
Scleral fragility
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should be
offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
UKGTN Testing Criteria
Test name:
Familial Porencephaly 2 Gene Panel
Approved name and symbol of disorder/condition(s):
Porencephaly 1; Poren1
Porencephaly 2; Poren2
Brain Small Vessel Disease with Hemorrhage
OMIM number(s):
175780
614483
607595
Approved name and symbol of gene(s):
collagen, type IV, alpha 1; COL4A1
collagen, type IV, alpha 2; COL4A2
OMIM number(s):
120130
120090
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Tick if this refers to
you.
Consultant Clinical Geneticist
Consultant Paediatric Neurologist
Consultant Neonatologist
Consultant Neurologist
Consultant in Stroke Medicine
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier:
Criteria
Tick if this patient
meets criteria
Evidence of familial porencephaly ie cysts or cavities within the cerebral
hemisphere AND
Hemiplegia, seizures and intellectual disability OR
Close family history of familial porencephaly
Additional Information:
At risk family members where familial mutation is known do not require a full panel test but should
be offered analysis of the known mutation
If the sample does not fulfil the clinical criteria or you are not one of the specified types of
referrer and you still feel that testing should be performed please contact the laboratory to
discuss testing of the sample.
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
Appendix 1
Genes in panel test and associated conditions. Highlighted rows indicate where the gene was currently being fully analysed in the context of a
single separate UKGTN test when the Gene Dossier was submitted.
ALPORT
HGNC standard
name and
symbol of the
gene
collagen, type IV, alpha 3
(Goodpasture antigen);
COL4A3
collagen, type IV, alpha
4; COL4A4
collagen, type IV, alpha
5; COL4A5
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
2204
ALPORT SYNDROME,
AUTOSOMAL DOMINANT
AD
104200
van der Loop et al. (2000) Kidney
Int. 58: 1870-1875 – 1 unique
variant in 6 individuals; Heidet et
al. (2001) J. Am. Soc. Nephrol. 12:
97-106 - 1 unique variant in 2
individuals
100
NO
Alport
ALPORT SYNDROME,
AUTOSOMAL
RECESSIVE
AR
203780
BENIGN FAMILAL
HAEMATURIA
AD
141200
ALPORT SYNDROME,
AUTOSOMAL
RECESSIVE
AR
203780
100
NO
Alport
BENIGN FAMILAL
HAEMATURIA
AD
141200
Mochizuki et al. (1994) Nature
Genet. 8: 77-81 - ; 3 unique
variant in 3 individuals Lemmink et
al. (1994) Hum Mol Genet 3: 12691273 - 1 unique variant in 1
individual; Gubler et al. (1995)
Kidney Int. 47: 1142-1147 – 15%
of Alport cases have mutations in
COL4A3 or COL4A4
Bandenas et al (2002) J AM Soc
Nephrol 13:1248-1254- 6/10
unrelated Spanish families had 2
different mutations in COL4A3
Mochizuki et al. (1994) Nature
Genet. 8: 77-81- 1 unique variant
in 1 individual; Gubler et al. (1995)
Kidney Int. 47: 1142-1147 – 15%
of Alport cases have mutations in
COL4A3 or COL4A4
Lemmink et al (1996) J Clin Invest
98: 1114-1118- Identified a
heterozygous mutation in COL4A4
ALPORT SYNDROME, XLINKED; ATS
XL
301050
100
YES
Alport
2206
2207
120070
120131
303630
Approval Date: September 2014
Knebelmann et al. (1996) Am. J.
Hum. Genet. 59: 1221-1232 - 74
variants in 131 individuals giving a
mutation detection rate of 50%;
Renieri et al. (1996) Am. J. Hum.
Genet. 58: 1192-1204 found
causative mutations in 45% of 201
unrelated individuals
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
COLLAGEN VI RELATED MYOPATHY
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
collagen, type VI, alpha
1; COL6A1
2211
120220
BETHLEM MYOPATHY
AD/AR
158810
Lucioli et al. (2005) Neurology 64:
1931-1937 – 8 unique variants in
16 individuals; Pan et al. (1998)
Hum. Molec. Genet. 7: 807-812 –
1 variant in a large American
pedigree
100
NO
Type VI related myopathy
AD/AR
254090
120240
ULLRICH CONGENITAL
MUSCULAR
DYSTROPHY; UCMD
BETHLEM MYOPATHY
AD
158810
Giusti et al (2005) Ann. Neurol. 58:
400-410 – 3 unique variants in 3
individuals
Baker et al. (2007) Ann. Neurol.
62: 390-405 – 2 unique variants in
2 individuals
100
NO
Type VI related myopathy
ULLRICH CONGENITAL
MUSCULAR
DYSTROPHY; UCMD
AD/AR
254090
BETHLEM MYOPATHY
AD
158810
100
NO
Type VI related myopathy
ULLRICH CONGENITAL
MUSCULAR
DYSTROPHY; UCMD
AD/AR
254090
Demir et al (2002) Am. J. Hum.
Genet. 70: 1446-1458 –
homozygous mutations in COL6A3
cause UCMD
collagen, type VI, alpha
2; COL6A2
collagen, type VI, alpha
3; COL6A3
2212
2213
120250
Venegas et al (2001) Proc. Nat.
Acad. Sci. 98: 7516-7521 demonstrated recessive mutations
in COL6A2 are the cause of
UCMD
Baker et al. (2007) Ann. Neurol.
62: 390-405 – 2 unique variants in
2 individuals
CUTIS LAXA
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
fibulin 5; FBLN5
3602
CUTIS LAXA,
AUTOSOMAL DOMINANT
2; ADCL2;
AD
614434
Callewaert et al (2013) Hum Mutat
34: 111-121 - 2 unique variants in
2 individuals
100
NO
Cutis Laxa
CUTIS LAXA,
AR
219100
Loeys et al. (2002) Hum. Molec.
604580
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
Elastin; ELN
3327
130160
EGF containing fibulinlike extracellular matrix
protein 2; EFEMP2
3219
604633
ATPase, H+ transporting,
lysosomal V0 subunit a2;
ATP6V0A2
18481
611716
pyrroline-5-carboxylate
reductase 1; PYCR1
9721
179035
latent transforming
growth factor beta
binding protein 4; LTBP4
6717
604710
ATPase, Cu++
transporting, alpha
polypeptide; ATP7A
869
300011
AUTOSOMAL
RECESSIVE, TYPE IA;
ARCL1A
CUTIS LAXA,
AUTOSOMAL DOMINANT
1; ADCL1
Genet. 11: 2113-2118 - 1 unique
variant in 4 individuals
AD
123700
SUPRAVALVULAR
AORTIC STENOSIS;
SVAS
AD
185500
CUTIS LAXA,
AUTOSOMAL
RECESSIVE, TYPE IB;
ARCL1B
CUTIS LAXA,
AUTOSOMAL
RECESSIVE, TYPE IIA;
ARCL2A
CUTIS LAXA,
AUTOSOMAL
RECESSIVE, TYPE IIB;
ARCL2B
AR
614437
AR
219200
AR
612940
CUTIS LAXA,
AUTOSOMAL
RECESSIVE, TYPE IIIB;
ARCL3B
AR
614438
CUTIS LAXA,
AUTOSOMAL
RECESSIVE, TYPE IC;
ARCL1C
OCCIPITAL HORN
SYNDROME; OHS
AR
613177
XL
304150
Szabo et al. (2006) 2 unique
variants in a 3 generation family;
Tassabehji et al. (1998) Hum Mol
Genet 7: 1021-1028 - 1 unique
variant in 1 individual
Micale et al. (2010) 7 unique
variants in 31 familal and sporadic
cases of SVAS
Hucthagowder et al. (2006) 1
unique variant in 1 individual;
Dasouki et al. (2007) 2 unique
variants in 1 individual
Kornak et al. (2008) 10 unique
variants in 12 families; Fischer et
al. (2012) 14 unique variants in 13
individuals
Reversade et al. (2009) Nature
Genet 41: 1016- 1023 - 16 unique
variants in 22 individuals
Lin et al. (2011) 2 unique variants
in 1 individual; Reversade et al.
(2009) 16 unique variants in 22
individuals
Callewaert et al (2013) Hum Mutat
34: 111-121 - 9 unique variants in
9 individuals; Urban et al. (2009) 5
unique variants in 4 individuals
Kaler et al. (1994) 1 unique variant
in1 individual; Tang et al. (2006) 1
unique variant in 2 individuals
100
NO
Cutis Laxa
100
NO
Cutis Laxa
100
NO
Cutis Laxa
100
NO
Cutis Laxa
100
NO
Cutis Laxa
100
YES
Cutis Laxa
EHLERS DANLOS SYNDROME
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
collagen, type III, alpha 1;
COL3A1
2201
EHLERS-DANLOS
SYNDROME, TYPE IV,
AUTOSOMAL DOMINANT
AD
130050
https://eds.gene.le.ac.uk/home.ph
p?select_db=COL3A1 ≥ 342
unique variants in 476 individuals
100
YES
EDS/FTAA
120180
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
collagen, type V, alpha 1;
COL5A1
2209
120215
EHLERS-DANLOS
SYNDROME, TYPE I;
EHLERS-DANLOS
SYNDROME, TYPE II
EHLERS-DANLOS
SYNDROME, TYPE I;
AD
130000;
130010
collagen, type V, alpha 2;
COL5A2
2210
120190
AD
130000
carbohydrate (Nacetylgalactosamine 4-0)
sulfotransferase 14;
CHST14
24464
608429
EHLERS-DANLOS
SYNDROME,
MUSCULOCONTRACTU
RAL TYPE 1; EDSMC1
AR
601776
procollagen-lysine, 2oxoglutarate 5dioxygenase 1; PLOD1
FK506 binding protein
14, 22 kDa; FKBP14
9081
153454
AR
225400
18625
614505
AR
614557
Ras and Rab interactor 2;
RIN2
18750
610222
EHLERS-DANLOS
SYNDROME, TYPE VI;
EDS6
EHLERS-DANLOS
SYNDROME WITH
PROGRESSIVE
KYPHOSCOLIOSIS,
MYOPATHY, AND
HEARING LOSS;
EDSKMH
MACROCEPHALY,
ALOPECIA, CUTIS LAXA,
AND SCOLIOSIS
AR
613075
PR domain containing 5;
PRDM5
9349
614161
BRITTLE CORNEA
SYNDROME 2; BCS2
AR
614170
zinc finger protein 469;
ZNF469
23216
612078
BRITTLE CORNEA
SYNDROME 1; BCS1
AR
229200
xylosylprotein beta 1,4galactosyltransferase,
polypeptide 7 ; B4GALT7
930
604327
AR
130070
solute carrier family 39
(zinc transporter),
member 13; SLC39A13
20859
608735
EHLERS-DANLOS
SYNDROME,
PROGEROID TYPE, 1;
EDSP1
SPONDYLOCHEIRODYS
PLASIA, EHLERSDANLOS SYNDROME-
AR
612350
Approval Date: September 2014
https://eds.gene.le.ac.uk/home.ph
p?select_db=COL5A1 ≥ 165
unique variants detected in 180
individuals
https://eds.gene.le.ac.uk/home.ph
p?select_db=COL5A2 ≥ 46 unique
variants detected in 45 individuals
https://eds.gene.le.ac.uk/home.ph
p?select_db=CHST14 ≥ 12 unique
variants detected in 17 individuals
100
YES
EDS
100
NO
EDS
100
NO
EDS
https://eds.gene.le.ac.uk/home.ph
p?select_db=PLOD1 ≥38 unique
variants detected in 65 individuals
Baumann et al. (2012) Am. J.
Hum. Genet. 90: 201-216 - 2
unique variants detected in 6
individuals
100
YES
EDS
100
NO
EDS
100
NO
EDS/Cutis Laxa
100
NO
EDS
100
NO
EDS
100
NO
EDS
100
NO
EDS
Basel-Vanagaite et al. (2009) Am.
J. Hum. Genet. 85: 254-263 - 1
unique variant in 3 individuals ;
Syx et al. (2010) Hum. Genet. 128:
79-88 - 1 unique variant in 3
individuals
Aldahmesh et al. (2012) Clin.
Genet. 81: 198-199 - 1 unique
variant in 1 individual Burkitt
Wright et al. (2011) Am. J. Hum.
Genet. 88: 767-777 - 2 unique
variants in 14 individuals
Abu et al. (2008) Am. J. Hum.
Genet. 82: 1217-1222 - 2 unique
variants detected in 5 individuals
Christensen et al. (2010) Invest.
Ophthal. Vis. Sci. 51: 47-52 - 1
unique variant detected in 2
individuals; Khan et al. (2010)
Arch. Ophthal. 128: 1376-1379 - 1
unique variants detected in
consanguineous family
https://eds.gene.le.ac.uk/home.ph
p?select_db=B4GALT7 ≥ 3 unique
variants detected in 2 individuals
Giunta et al. (2008) Am. J. Hum.
Genet. 82: 1290-1305 - 1 unique
variants detected in 6 individuals
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
LIKE
ADAM metallopeptidase
with thrombospondin type
1 motif, 2; ADAMTS2
218
604539
EHLERS-DANLOS
SYNDROME, TYPE VII,
AUTOSOMAL
RECESSIVE
AR
225410
Fukada et al. (2008) PLoS One 3:
e3642 - 1 unique variants detected
in 2 individuals
https://eds.gene.le.ac.uk/home.ph
p?select_db=ADAMTS2 ≥ 20
variants detected
100
NO
EDS
COLLAGEN 4 RELATED DISORDERS
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
collagen, type IV, alpha
1; COL4A1
2202
PORENCEPHALY 1;
POREN1
AD
175780
Gould et al. (2005) Science 308:
1167-1171 - 2 unique variants
detected in 2 families; Breedveld
et al (2005) J Med Genet 43: 490495 - 3 unique variants in 10
individuals
100
NO
Type IV related disorders
BRAIN SMALL VESSEL
DISEASE WITH
HEMORRHAGE
PORENCEPHALY 2;
POREN2
AD
607595
Sibon et al. Ann. Neurol. 62: 177184, 2007
AD
614483
Yoneda et al. (2012) Am. J. Hum.
Genet. 90: 86-90 - 2 unique
variants detected in 2 individuals
100
NO
Type IV related disorders
collagen, type IV, alpha
2; COL4A2
2203
120130
120090
FAMILAL THORACIC AORTIC ANEURYSMS
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
Actin, alpha 2, smooth
muscle, aorta; ACTA2
130
AORTIC ANEURYSM,
FAMILIAL THORACIC 6
AD
611788
Guo Nature Genet. 39: 1488-1493,
2007
14%of inherited ascending
thoracic aneurysms and
dissections.
100
No
FTAA
613834
Milewicz Am. J. Med. Genet.
102620
MULTISYSTEMIC
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
SMOOTH MUSCLE
DYSFUNCTION
SYNDROME
Fibrillin 1; FBN1
3603
134797
MARFAN SYNDROME
AD
154700
myosin, heavy chain 11,
smooth muscle; MYH11
7569
160745
AORTIC ANEURYSM,
FAMILIAL THORACIC 4
AD
132900
solute carrier family 2
(facilitated glucose
transporter), member 10;
SLC2A10
filamin A, alpha; FLNA
SMAD family member;
SMAD3
Fibrillin 2; FBN2
13444
3754
6769
3604
606145
300017
603109
612570
ARTERIAL TORTUOSITY
SYNDROME
HETEROTOPIA,
PERIVENTRICULAR,
EDS VARIANT
LOEYS-DIETZ
SYNDROME, TYPE 3
CONTRACTURAL
Approval Date: September 2014
AR
208050
X-linked
AD
AD
300537
613795
121050
152A: 2437-2443, 2010
Seven unrelated patients
presenting with multisystemic
smooth muscle dysfunction
syndrome
Comeglio et al. Hum. Mutat. 28:
928 , 2007.
508 individuals:
90 (82%) of 110 patients with
'classic' Marfan;
84 (27%) of 315 with 'incomplete
Marfan phenotype;
19 (50%) of 38 patients with
isolated ectopia lentis.
Pannu Hum. Molec. Genet. 16:
2453-2462, 2007
Two kindreds with thoracic aortic
aneurysm and/or aortic dissection.
Zhu Nature Genet. 38: 343-349,
2006
Three probands from 3 TAAD
families
Couke J. Med. Genet. 40: 747751, 2003
Mutations identified in 6 ATS
families
Callewaert Hum. Mutat. 29: 150158, 2008
16 patients from 12 families, 11
different mutations identified.
Sheen Neurology 64: 254-262,
2005
Two families and 9 sporadic cases
reported.
Gomez-Garre J. Med. Genet. 43:
232-237, 2006
Three female patients from a 3generation Spanish family
Van de Laar J. Med. Genet. 49:
47-57, 2012
Data from 45 patients from 8
families presented.
Regalado
Circ. Res. 109: 680-686, 2011
Concludes SMAD3 mutations
found in 2%of FTAA
Frederic Hum Mutat 30(2) 181-190
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
100
Yes
FTAA
100
No
FTAA
100
No
FTAA
100
No
FTAA
100
No
FTAA
100
No
FTAA
ARACHNODACTYLY,
CONGENITAL
transforming growth
factor, beta 2; TGFB2
11768
190220
LOEYS-DIETZ
SYNDROME, TYPE 4
transforming growth
factor, beta receptor 1;
TGFBR1
11772
190180
LOEYS DIETZ
SYNDROME
609192
FAMILIAL THORACIC
AORTIC ANEURYSMS
608967
transforming growth
factor, beta receptor 2;
TGFBR2
11773
190182
AD
614816
LOEYS-DIETZ
SYNDROME, TYPE 1B
610168
LOEYS-DIETZ
SYNDROME, TYPE 2B
610380
2009
Locus specific database ≥115
records provided.
Lindsay Nature Genet. 44: 922927, 2012
86 individuals – 6 mutations
identified
Loeys New Eng. J. Med. 355: 788798, 2006
13 mutations identified in cohort of
80; 40 with typical manifestations,
40 with apparent vascular EDS.
Singh Hum. Mutat. 27: 770-777,
2006
41 unrelated individuals 2
mutations in TGFBR1 and 5 in
TGFBR2 identified
Stheneur Hum Mutat.
2008;29:E284–95
Investigations in 457 patients with
Marfan syndrome type I and II,
Loeys-Dietz syndrome and related
disorders - 23 TGFBR2 and 6
TGFBR1 mutations identifed
100
No
FTAA
100
Yes
FTAA
100
Yes
FTAA
OSTEOGENESIS IMPERFECTA
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
collagen, type I, alpha 1;
COL1A1
2197
OSTEOGENESIS
IMPERFECTA, TYPE I
AD
166200
https://oi.gene.le.ac.uk/home.php?
select_db=COL1A1
100
Yes
OI/EDS
OSTEOGENESIS
IMPERFECTA, TYPE II
166210
≥1360 individuals with OI listed
with variants in this gene
OSTEOGENESIS
IMPERFECTA, TYPE III
259420
OSTEOGENESIS
IMPERFECTA, TYPE IV
166220
EHLERS-DANLOS
SYNDROME, TYPE VIIA
120150
120150
Approval Date: September 2014
6 individuals with EDS VIIA
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
collagen, type I, alpha 2;
COL1A2
Cartliage-associated
protein; CRTAP
2198
2379
120160
605497
EHLERS-DANLOS
SYNDROME, TYPE I
OSTEOGENESIS
IMPERFECTA, TYPE I
130000
11 individuals OI/EDS overlap
166200
https://oi.gene.le.ac.uk/home.php?
select_db=COL1A2
OSTEOGENESIS
IMPERFECTA, TYPE II
166210
≥798 OI individuals with variants in
this gene
OSTEOGENESIS
IMPERFECTA, TYPE III
259420
OSTEOGENESIS
IMPERFECTA, TYPE IV
166220
EHLERS-DANLOS
SYNDROME, TYPE VIIB
120160
26 individuals with EDS VIIB
AR
225320
11 individuals OI/EDS overlap
AR
610682
https://oi.gene.le.ac.uk/home.php?
select_db=CRTAP
EHLERS-DANLOS
SYNDROME, CARDIAC
VALVULAR FORM
OSTEOGENESIS
IMPERFECTA, TYPE VII
AD
interferon induced
transmembrane protein
5; IFITM5
1664
614757
OSTEOGENESIS
IMPERFECTA, TYPE V
AD
610967
Leucine proline-enriched
proteoglycan (leprecan)
1; LEPRE1
19316
610339
OSTEOGENESIS
IMPERFECTA, TYPE VIII
AR
610915
≥25 individuals with variants in this
gene
https://oi.gene.le.ac.uk/home.php?
select_db=IFITM5
≥32 individuals reported
https://oi.gene.le.ac.uk/home.php?
select_db=LEPRE1
≥48 individuals with variants in this
gene
https://oi.gene.le.ac.uk/home.php?
select_db=PPIB
100
Yes
OI/EDS
100
No
OI
Formerly known as OI
type IIB
N/A
No
OI
A single point mutation is
report in OI type V
100
No
OI
100
No
OI
100
No
OI
peptidylprolyl isomerase
B (cyclophilin B); PPIB
9255
123841
OSTEOGENESIS
IMPERFECTA, TYPE IX
AR
259440
serpin peptidase inhibitor,
clade F (alpha-2
antiplasmin, pigment
epithelium derived
factor), member 1;
SERPINF1
serpin peptidase inhibitor,
clade H (heat shock
protein 47), member 1,
(collagen binding protein
1); SERPINH1
FK506 binding protein
10, 65 kDa; FKBP10
8824
172860
OSTEOGENESIS
IMPERFECTA, TYPE VI
AR
613982
1546
600943
OSTEOGENESIS
IMPERFECTA, TYPE X
AR
613848
Christiansen et al Am J Hum
Genet 2010 86(3):389-98
Single severely affected individual
reported.
100
No
OI
18169
607063
OSTEOGENESIS
IMPERFECTA, TYPE XI
AR
610968
https://oi.gene.le.ac.uk/home.php?
select_db=FKBP10
100
No
OI
Approval Date: September 2014
≥12 individuals reported
https://oi.gene.le.ac.uk/home.php?
select_db=SERPINF1
≥21 individuals reported
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
≥48 individuals reported
BRUCK SYNDROME 1
procollagen-lysine, 2oxoglutarate 5dioxygenase 2; PLOD2
Sp7 transcription factor;
SP7
9082
601865
BRUCK SYNDROME 2
AR
609220
17321
606633
OSTEOGENESIS
IMPERFECTA, TYPE XII
AR
613849
transmembrane protein
38B; TMEM38B
25535
611236
OSTEOGENESIS
IMPERFECTA, TYPE XIV
AR
615066
wingless-type MMTV
integration site family,
member 1; WNT1
12774
164820
OSTEOGENESIS
IMPERFECTA, TYPE XV
100
No
There is clinical overlap
between OI and Bruck
syndrome.
OI
100
No
OI
100
No
OI
100
No
OI
100
No
OI
100
No
OI
100
No
OI
259450
AR
615220
https://oi.gene.le.ac.uk/home.php?
select_db=PLOD2
≥10 individuals described
Lapimzina et al 2010 Am J Hum
Genet
Case report
Shaheen J. Med. Genet. 49: 630635, 2012
Three consanguineous families
reported.
Volodarsky et al Hum. Mutat. 34:
582-586, 2013
A further three consanguineous
families
KeuppAm. J. Hum. Genet. 92:
565-574, 2013
Three individuals from one family.
Pyott Am. J. Hum. Genet. 92: 590597, 2013
Four families
Fahiminiya J. Med. Genet. 50:
345-348, 2013
Three families
bone morphogenetic
protein 1; BMP1
1067
112264
Plastin 3; PLS3
9091
300131
cAMP responsive
element binding protein
3-like 1 CREB3L1
18856
Not assigned
OSTEOPOROSIS,
EARLY-ONSET,
SUSCEPTIBILITY TO,
AUTOSOMAL DOMINANT
OSTEOGENESIS
IMPERFECTA, TYPE XIII
X-LINKED
OSTEOPOROSIS AND
FRACTURES
OSTEOGENESIS
IMPERFECTA, TYPE III
Approval Date: September 2014
615221
AR
614856
X-linked
300910
AR
259420
Laine New Eng. J. Med. 368:
1809-1816, 2013
Case study
Asharani Am. J. Hum. Genet. 90:
661-674, 2012
Two affected sibs from
consanguineous family.
Martinez-Glez Hum. Mutat. 33:
343-350, 2012
Two sibs in consanguineous family
Van Dijk New Eng. J. Med. 369:
1529-1536, 2013
Five families segregating
Symoens Orphanet J Rare Dis
8;154
Case report
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
STICKLER
HGNC standard
name and
symbol of the
gene
HGNC
OMIM
number number
OMIM standard
name of condition
and symbol
Mode
of
inherit
ance
OMIM
number
Evidence of
association between
gene(s) and condition
% of
horizontal
coverage
of gene
MLPA
Comments
collagen, type XI, alpha
1; COL11A1
2186
120280
STICKLER SYNDROME,
TYPE II; STL2
AD
604841
100
YES
Stickler/Marshall
collagen, type XI, alpha
2; COL11A2
2187
120290
STICKLER SYNDROME,
TYPE III; STL3
AD
184840
100
NO
Stickler
collagen, type II, alpha 1;
COL2A1
2200
120140
STICKLER SYNDROME,
TYPE I,
NONSYNDROMIC
OCULAR
AD
609508
Annunen et al. (1999) Am. J. Hum.
Genet. 65: 974-983 - 15 unique
variants in 15 individuals ; Majava
et al. (2007) Am J Med Genet
143A:258–264 - 10 unique
variants in 10 individuals
Vikkula et al. (1995) Cell 80: 431437 - 1 unigue variant in a large
Dutch kindred segregating with
Stickler; Vuoristo et al. (2004) Am.
J. Med. Genet. 130A: 160-164 - 1
unique variant in a 3 generation
family with Stickler
Richards et al. (2006) Hum. Mutat.
27: 696-704 - 3 unique variants in
3 families; McAlinden et al. (2008)
Hum. Mutat. 29: 83-90 - 2 unique
variants in 3 individuals
100
YES
Stickler/Achondrogenesis
STICKLER SYNDROME,
TYPE I; STL1
AD
108300
STICKLER SYNDROME,
TYPE IV; STL4
AR
614134
100
NO
Stickler
EPIPHYSEAL
DYSPLASIA, MULTIPLE,
6; EDM6
STICKLER SYNDROME,
TYPE V; STL5
AD
614135
AR
614284
100
NO
Stickler
EPIPHYSEAL
DYSPLASIA, MULTIPLE,
2; EDM2
AD
600204
EPIPHYSEAL
DYSPLASIA, MULTIPLE,
3; EDM3
AD
600969
100
NO
Stickler
collagen, type IX, alpha
1; COL9A1
collagen, type IX, alpha
2; COL9A2
collagen, type IX, alpha
3; COL9A3
2217
2218
2219
120201
120260
121270
Approval Date: September 2014
Annunen et al. (1999) Am. J. Hum.
Genet. 65: 974-983 - 8 unique
variants in 8 individuals; Richards
et al. (2006) Hum. Mutat. 27: 696704 - 47 variants in 50 individuals
Van Camp et al. (2006) Am. J.
Hum. Genet. 79: 449-457 - 1
unique variant in 1 individual
Czarny-Ratajczak et al. (2001)
Am. J. Hum. Genet. 69: 969-9801 unique variant in 1 individual
Baker et al. (2011) Am. J. Med.
Genet. 155A: 1668-1672 – 1
unique variant segregating in a 5
generation family
Fiedler et al. (2002) Am. J. Med.
Genet. 112: 144-153 – 1 unique
variant in 12 affected members of
a 5 generation family
Paassilta et al. (1999) Am. J. Hum.
Genet. 65: 1214 – 1 unique variant
in several affected members of a
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
procollagen-lysine, 2oxoglutarate 5dioxygenase 3; PLOD3
9083
603066
solute carrier family 26
(anion exchanger),
member 2; SLC26A2
10994
606718
family with EDM3
https://eds.gene.le.ac.uk/home.ph
p?select_db=PLOD3 ≥ 3 unique
variants in 2 individuals
BONE FRAGILITY WITH
CONTRACTURES,
ARTERIAL RUPTURE,
AND DEAFNESS
EPIPHYSEAL
DYSPLASIA, MULTIPLE,
4; EDM4
AR
612394
AR
226900
Czarny-Ratajczak et al. (2001)
Am. J. Hum. Genet. 69: 969-980 –
1 unique variant in 2 individuals;
Ballhausen et al. (2003) J. Med.
Genet. 40: 65-71 – 1 unique
variant in 18 individuals from 12
families
ACHONDROGENESIS,
TYPE IB; ACG1B
AR
600972
Superti-Furga et al. (1996) Nature
Genet. 12: 100-102 – 6 variants in
6 individuals
Approval Date: September 2014
Submitting Laboratory: Sheffield RGC
Copyright UKGTN © 2014
100
NO
Stickler
100
NO
Stickler/Achondrogenesis