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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: [email protected]
www.genedx.com
Test Information Sheet
Zone of Polarizing Activity Regulatory Sequence (ZRS) in the LMBR1 Gene
in Triphalangeal Thumb Polydactyly
Including: Triphalangeal thumb polydactyly, preaxial polydactyly II (PPD2), Werner mesomelic syndrome,
Haas type syndroactyly (syndactyly type IV), and Laurin-Sandrow syndrome
Mendelian Inheritance in Man Number: 605522 (LMBR1 gene, including ZRS); 174500 (preaxial polydactyly
II); 188770 (Werner mesomelic syndrome; tibial hypoplasia-polysyndactyly-triphalangeal thumb); 186200
(Haas type, syndactyly type IV); 135750 (Laurin-Sandrow syndrome)
Clinical features:
Triphalangeal thumb (TPT) is the hallmark feature in individuals with mutations in the zone of polarizing
activity regulatory sequence (ZRS), which is contained within intron 5 of the LMBR1 gene. Mutations in ZRS
have been reported in individuals with PPD2 (TPT with or without preaxial polydactyly), TPT
polysyndactyly, syndactyly IV (complete syndactyly with polydactyly), Werner mesomelic syndrome (tibial
hypoplasia, polysyndactyly, TPT), and Laurin-Sandrow syndrome (mirror-image polysyndactyly, nasal
defects).
Inheritance pattern:
Autosomal dominant with variable expressivity.
Genetics/Mutation Spectrum:
ZRS, or zone of polarizing activity (ZPA) regulatory sequence, is a long range regulator of the SHH gene.
ZRS is located on chromosome 7q36.3 residing in intron 5 of the LMBR1 gene, approximately 1Mb
upstream of the SHH gene. ZRS is evolutionarily conserved among mammals and fish and regulates the
timing and spatial expression of SHH for limb patterning. Gain-of-function mutations within ZRS have
been reported in the literature including point mutations and duplications.
Reasons for referral:
 Confirmation of a clinical diagnosis
 Differentiation from other causes of syndromic and isolated limb abnormalities
 Genetic counseling and recurrence risk assessment
 Prenatal diagnosis in families with a known mutation
Test method:
For those individuals with clinical features suggestive of a ZRS-related disorder, using genomic DNA
obtained from the submitted biological material, bi-directional sequence of the ZRS region is obtained
and analyzed. If no mutation is identified by sequence analysis, deletion/duplication analysis can be
performed by targeted array comparative genomic hybridization (aCGH) analysis with exon-level
resolution (ExonArrayDx). Mutations/deletions/duplications found in the first person of a family to be
tested are confirmed by repeat analysis using sequencing, restriction fragment analysis, qPCR, or other
appropriate method.
Information Sheet for ZRS in LMBR1 Gene
Page 1 of 2
© GeneDx
12/2014
Test sensitivity
Mutations in ZRS have been identified in approximately 2-3% of individuals with congenital limb
malformations (Furniss et al., 2008; Furniss et al., 2009).
Specimen Requirements and Shipping/Handling:
 Blood: A single tube with 1-5 mL whole blood in EDTA. Ship overnight at ambient temperature,
using a cool pack in hot weather. Specimens may be refrigerated for 7 days prior to shipping.
 Buccal Brushes: Cannot be accepted.
 Prenatal Diagnosis: For prenatal testing for a known mutation in the ZRS gene, please refer to the specimen
requirements table on our website at: http://www.genedx.com/test-catalog/prenatal/. Ship specimen overnight
at ambient temperature, using a cool pack in hot weather.
Required Forms:
 Sample Submission (Requisition) Form – complete all pages
 Payment Options Form or Institutional Billing Instructions
For test codes, prices, CPT codes, and turn-around-times, please refer to the “Triphalangeal Thumb Polydactyly”
page on our website: www.genedx.com
References cited:
Furniss et al., (2008) Hum Mol Genet 17(16):2417-2423; Furniss et al., (2009) J Med Genet 46:730-735;
Gurnett et al., (2007) Am J Med Genet Part A 143A:27-32; Klopocki et al., (2008) J Med Genet 45:370-375;
Semerci et al., (2009) Clin Genet 76:85-90; Sun et al., (2008) J Med Genet 45:589-595; Wieczorek et al.,
(2010) Hum Mutat 31(1):81-89; Wu et al., (2009) Am J Med Genet Part A 149A:816-818; Lohan et al.,
(2014) Clin Genet 86(4):318-325.
Information Sheet for ZRS in LMBR1 Gene
Page 2 of 2
© GeneDx
12/2014