Download Genetic Testing for Non-Cancerous Inheritable Diseases

Genetic Testing for Non-Cancerous Inheritable Diseases
I.
Policy
University Health Alliance (UHA) will reimburse for Genetic Testing for Non-Cancerous Inheritable Diseases
when determined to be medically necessary and within the medical criteria guidelines (subject to limitations
and exclusions) indicated below.
II. Criteria/Guidelines
A. Genetic testing for all the inheritable diseases listed below must meet the following criteria (in addition
to any specific criteria) in order to be covered:
1. There must be a reasonable expectation based on family history, pedigree analysis, risk
factors, and/or symptomatology that a genetically inherited condition exists.
2. The genotypes to be detected by a genetic test must be shown by scientifically valid methods
to be associated with the occurrence of the disease.
3. The analytical and clinical utility validity of the test must be established (e.g., test results will
influence decisions concerning disease treatment or prevention).
B. Genetic testing is covered (subject to Limitations/Exclusions and Administrative Guidelines) if after
history, physical exam, pedigree analysis, and completion of conventional diagnostic studies, a
definitive diagnosis remains uncertain and one of the following diagnoses are suspected. These
include but are not limited to:
•
•
Achrondroplasia (FGFR3)
•
Amino acid metabolic disturbances
•
Classical lissencephaly
•
Congenital hydrocephalus
•
Charcot-Marie Tooth disease (PMP22)
Cri-du-chat
•
Fabry disease
Cystic kidney disease (including
polycystic kidney, autosomal
dominant)
Gonadal dysgenesis (Turner’s, XO
syndrome)
•
Down's syndrome
•
Dwarfism
•
Factor XIII (F13) deficiency,
congenital (Factor XIII beta globulin)
•
Friedreich’s ataxia (FRDA [frataxin])
•
Von Willebrand’s disease
•
Neurofibromatosis type 2 (Merlin)
•
•
Osteogenesis imperfecta
•
Phenylketonuria (PKU)
Prader-Willi-Angelman syndrome
(SNRPN, GABRA5, NIPA1, UBE3A,
ANCR, GABRA)
•
Peutz-jeghers
•
Thanatophoric dysplasia (FGFR3)
•
Tuberous sclerosis
•
Turners syndrome
•
Velo cardio facial syndrome(catch
22)
•
Von Hippel-Lindau syndrome (VHL)
•
Hereditary progressive muscular dystrophy (Duchene[dystrophin]-Becker’s type(limb girdle muscular dystrophy [LGMD1,
LGMD2])-Oculopharyngeal muscular dystrophy [OPMD]))
•
•
Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy
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The following genetic tests are covered (subject to Limitations/Exclusions and Administrative Guidelines) with prior
authorization:
C. Genetic testing for cystic fibrosis (CF)
1.
Genetic testing for cystic fibrosis using the American College of Medical Genetics (ACMG)
mutation core panel (AMCG 23) for preconception or prenatal carrier testing of an individual
who is pregnant or a prospective biologic parent with the capacity and desire to reproduce.
2.
Complete analysis of the cystic fibrosis gene if covered (subject to Limitations and Exclusions)
in the following:
a. For patients with cystic fibrosis
b. Patients with a family history of cystic fibrosis
c. Males with congenital bilateral absence of the vas deferens
d. Newborns with a positive newborn screening result when mutations testing, using the
standard 23-mutations panel, has a negative result.
D. Chromosomal microarray analysis as first line testing in initial postnatal evaluation of individuals with
any of the following:
1. Apparently nonsyndromic developmental delay/intellectual disability.
2. Autism Spectrum Disorder
3. Multiple congenital anomalies not specific to a well-delineated genetic syndrome
E. Genetic testing for carrier status of spinal muscular atrophy (SMA) in high-risk individuals when ordered
by a geneticist or pediatric neurologist meeting any of the following criteria:
1. Individuals with a positive family history of SMA, limited to first- or second-degree relatives
2. Reproductive partner of an individual with SMA or is a known SMA carrier
3. Individuals with a first-degree relative identified as a SMA carrier
F. Genetic testing for FMR1 mutations (including fragile X syndrome) for individuals in any of the following
risk categories where the results of the test will affect clinical management or reproductive decisions:
1. Individuals with an intellectual disability, DD, or ASD
2. Prenatal testing of fetuses of known carrier mothers
3. Individuals planning a pregnancy who have either of the following;
a. A first- or second-degree relative with fragile X syndrome, or
b. A first- or second-degree relative with undiagnosed intellectual disability
G. carrier screening for Ashkenazi Jewish individuals for:
1. Tay-Sachs disease
2. Canavan disease
3. Familial Dysautomia
4. Fanconi anemia
5. Niemann-Pick (Type A)
6. Bloom Syndrome
7. Gaucher disease
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8. Mucolipidosis IV
H. Genetic testing for HFE-gene mutations related to hereditary hemochromatosis (HHC):s:
1. For diagnostic testing when the individual with symptoms consistent with hemochromatosis
and serum transferrin iron saturation is greater than or equal to 45%, but the diagnosis remain
uncertain after completion of conventional testing
2. In individuals with a family history of hemochromatosis in a first degree relative.
I.
Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) for individuals having one firstdegree relative with established HCM when there is a known pathogenic gene mutation present in that
affective relative.
J. Genetic testing for suspected congenital Long QT Syndrome (LQTS) for individuals who do not meet
the clinical criteria for LQTS but have one of the following:
1. A first- or second-degree relative with a known LQTS mutation
2. A first- or second-degree relative diagnosed with LQTS by clinical means whose genetic status
is unavailable
3. Signs and/or symptoms indicating a moderate to high pretest probability of LQTS, defined as a
Schwartz score of 2-3. (See Table I in the Appendix)
K. Genetic testing for Factor V Leiden and/or prothrombin G20210A mutation when any of the following
criteria are met:
1. Age less than 50, any venous thrombosis, and in patients who develop acute arterial
thrombosis in the absence of other risk factors for atherosclerotic arterial occlusive disease
2. Recurrent venous thrombosis
3. Venous thrombosis and a first-or second-degree relative with thrombotic disease
4. Venous thrombosis in pregnant women or women taking oral contraceptives. Women with
recurrent pregnancy loss or unexplained severe preeclampsia, placental abruption,
intrauterine fetal growth retardation or sillbirth.
5. Myocardial infarction in female smokers under age 50
L. Genotypic or phenotypic analysis of the Thiopurine Methyltransferase (TPMT) gene is covered on a one
time basis in patients beginning therapy with azathioprine (AZA), mercaptopurine (6-MP) or thioguanine
(6-TG), or in patients on thiopurine therapy with abnormal complete blood count results that do not
respond to dose reduction. .
M. Genetic testing for hemoglobinopathies (i.e., thalassemias and sickle cell disease) is covered when one
of the following criteria are met:
1. For confirmation of a diagnosis in either of the following situations:
a. Individuals with clinical features suggestive of a hemoglobinopathy when test results
from conventional studies (e.g., electrophoresis, anemia, iron deficiency) are
inconclusive and have failed a trial of iron therapy
b. Infants who are diagnosed on newborn screening as having a hemoglobinopathy
2. For carrier testing in either of the following situations:
a. When there is an affected first- or second-degree relative that has thalassemia or
sickle cell disease.
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b. When the patient is the reproductive partner of a known carrier (disease-causing
mutation of gene HBB, HBA1, or HBA2) and the couple has the capacity and
intention to reproduce.
N. Because of the rapidly evolving field of genetic testing, this policy does not address every genetic test
available. All other conditions not mentioned in this policy will be reviewed based on medical necessity
and the policy criteria (IIA 1-3).
III. Limitations/Exclusions
A. The following genetic tests are not covered because they have not been shown to improve health
outcomes (this list is not all inclusive):
1. Genetic testing to determine preterm labor
2. Genetic testing to determine Warfarin sensitivity
3. Genetic testing for the diagnosis or risk assessment of Alzheimer's disease including but not
limited to testing for, apolipoprotein E epsilon 4 allele, presenilin genes or amyloid precursor
gene
4. Genetic testing for helicobacter pylori treatment
5. MTHFR polymorphism testing
B. Genetic testing is not covered in the following circumstances:
1. Family members of subscribers, who themselves are not subscribers or dependents
2. Members if the results of the genetic testing are for the benefit of relatives who are not
subscribers or dependents
C. If a patient has been screened previously, CF screening results should be documented and the test
should not be repeated.
D. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier
screening.
E. Except as referenced in Criteria/Guidelines, genetic screening of individuals is not covered in the
absence of associated signs, symptoms or complaints. General population screening for genetic
disorders is not covered except where mandated by State and Federal law.
F. Laboratories that conduct genetic testing must be CLIA certified.
G. UHA will cover pre and post test genetic counseling with a physician or a certified genetic counselor
as medically necessary for an individual recommended for covered heritable genetic testing.
H. Genetic tests for a specific inherited disease will be covered once per lifetime unless new techniques
that increase sensitivity are utilized.
I.
Home genetic testing is not a covered benefit.
J. For a known deleterious mutation, UHA will only cover a targeted single site analysis genetic test not
a full analysis (i.e., testing for the mutation that has been identified in the family).
K. Chromosomal microarray analysis is not covered to confirm the diagnosis of a disorder or syndrome
that is routinely diagnosed based on clinical evaluation alone.
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L. The following expanded prenatal panel tests are not covered because the clinical utility has not been
established: (This is not an all-inclusive list)
1. Counsyl
2. GoodStart Select
3. Inherigen
4. Inheritest
5. Natera One Disease Panel
6. Progenity CFnxt
M. NOTE:
This UHA payment policy is a guide to coverage, the need for prior authorization and other
administrative directives. It is not meant to provide instruction in the practice of medicine and it
should not deter a provider from expressing his/her judgment.
Even though this payment policy may indicate that a particular service or supply is considered
covered, specific provider contract terms and/or member’s individual benefit plans may apply, and
this policy is not a guarantee of payment UHA reserves the right to apply this payment policy to all
UHA companies and subsidiaries.
UHA understands that opinions about and approaches to clinical problems may vary. Questions
concerning medical necessity (see Hawaii Revised Statutes §432E-1.4) are welcome. A provider
may request that UHA reconsider the application of the medical necessity criteria in light of any
supporting documentation.
IV. Administrative Guidelines
A. Prior authorization for the genetic tests is required and must be submitted by a properly
certified/licensed and credentialed genetic specialist (i.e., board certified neurologist (MD), boardcertified medical geneticist (MD), board-certified clinical geneticist (PhD), board-certified genetic
counselor (MS and/or CGC), or licensed advanced practice registered nurse in genetics (APRN).)
B. Complete UHA’s Prior Authorization Request and Notification Form and include the following
information:
1. Specify the condition for which the genetic test is being performed and if there are any known
first- or second-degree relatives with the condition
2. Other types of biochemical testing apart from molecular genetic testing (enzyme activity
assays, hemoglobin electrophoresis, blood chemistries, etc.), phenotypic findings and relevant
clinical history and exam details
3. Specify how the results of the genetic test will impact the clinical management of the patient in
terms of improving health outcomes
C. To request prior authorization, please go to UHA’s website: https://uhahealth.com/page/priorauthorization-forms#pa-medical or you may submit an electronic prior authorization at
https://uhahealth.com/page/prior-authorization-forms and submit it:
Via Fax: 1-866-572-4384
Via Mail:
UHA Health Care Services
700 Bishop Street, Suite 300
Honolulu, HI 96813
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D. Applicable HCPCS and ICD-9 codes requiring prior authorization:
HCPCS
Code
Description
S3845
Genetic testing for alpha-thalassemia
S3846
Genetic testing for hemoglobin E beta-thalassemia
S3850
Genetic testing for sickle cell anemia
S3861
Genetic testing, sodium channel, voltage-gated, type V, alpha subunit (SCN5A) and variants for
suspected Brugada Syndrome
S3865
Comprehensive gene sequence analysis for hypertrophic cardiomyopathy
S3866
Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual
with a known HCM mutation in the family
S3870
Comparative genomic hybridization (CGH) microarray test for developmental delay/ autism spectrum
disorder and/or mental retardation
ICD-9
Codes
Description
272.7
Lipidoses
275.01
Hereditary hemochomatosis
277.00277.09
Cystic Fibrosis (CTFR)
282.40 282.49
Thalassemia(alpha globin/beta globin/hemoglobin E)
282.5
Sickle-cell trait (hemoglobin S)
282.61
Hb-SS disease without crisis
282.62
Hb-SS disease with crisis
282.63
Sickle-cell/Hb-C disease
282.7
Other hemoglobinopathies (hemoglobin C)
299.00299.01
Autistic disorder, current or active state or residual state
317-319
Mental retardation
330.1
Cerebral lipidoses (Tay-Sachs disease)
335.10335.19
Spinal muscular atrophy (SBMA,SMN)
425.11
Hypertrophic obstructive cardiomyopathy
425.18
Other hypertrophic cardiomyopathy
425.4
Other primary cardiomyopathies (including familial and hypertrophic cardiomyopathy not otherwise
specified)
426.82
Long QT syndrome
555.0555.9
Regional enteritis
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556.0556.9
Ulcerative colitis
643.30
Habitual aborter; unspecified, with or without mention of antepartum condition (defined as two or more
consecutive pregnancy losses)*
646.33
Habitual aborter; antepartum condition or complication(defined as two or more consecutive pregnancy
losses)*
746.89
Other congenital anomalies of the heart (Brugada syndrome)
759.83
Fragile X syndrome
783.42
Delayed milestone
V12.51
Personal history of venous thrombosis and embolism
V17.41
Family history of sudden cardiac death (SCD)
V17.49
Family history of other cardiovascular diseases
V18.9
Family history of genetic disease carrier
V19.5
Family history of congenital anomalies
V26.31
Genetic testing of female for genetic disease carrier status
V26.34
Genetic testing of male for genetic disease carrier status
V77.6
Special screening for cystic fibrosis
V77.7
Special screening for other inborn errors of metabolism
V77.91
Screening for lipoid disorders
V79.2
Special screening for mental retardation
V82.4
Maternal postnatal screening for chromosomal anomalies
V83.81
Cystic fibrosis gene carrier
V83.89
Other genetic carrier screening
V84.89
Genetic susceptibility to other disease
E. These codes are no longer effective for services rendered after 04/01/2012
HCPCS
Description
S3835
Complete gene sequence analysis for cystic fibrosis genetic testing
S3837
Complete gene sequence analysis for hemochromatosis genetic testing
S3843
DNA analysis of F5 gene for susceptibility to Factor V Leiden thrombophilia
S3847
Genetic testing for Tay-Sachs disease
S3848
Genetic testing for Gaucher disease
S3851
Genetic testing for Canavan disease
S3860
Genetic testing, comprehensive cardiac ion channel analysis, for variants in 5 major cardiac ion
channel genes for individuals with high index of suspicion for familial LQTS or related syndromes
S3862
Genetic testing, family-specific ion channel analysis, for blood-relatives of individuals (index case)
who have previously tested positive for a genetic variant of a cardiac ion channel syndrome using
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either one of the above test configurations or confirmed results from another laboratory.
* Definition from the American College of Obstetricians and Gynecologists: Practice Bulletin #24
F. HCPCS and ICD-9 codes that do not require prior authorization
HCPCS
Code
Description
S3842
Genetic testing for Von Hippel-Lindau disease
S3849
Genetic testing for Niemann-Pick disease
S3853
Genetic testing for myotonic muscular dystrophy
ICD-9
Code
Description
237.71
Neurofibromatosis, type 1 (neurofibromin)
237.72
Neurofibromatosis, type 2 (Merlin)
259.4
Dwarfism, not elsewhere classified [hypochondroplasia , thanatophoric dysplasia (FGFR3)]
270.1
Phenylkentonuria (PKU)
270.2
Other disturbances of aromatic amino-acid metabolism (includes albinism)
270.3
Disturbances of branched-chain amino acid metabolism (includes maple syrup urine disease)
270.4
Disturbances of suphur-bearing amino-acid metabolism (includes homocystinuria)
277.5
Mucopolysaccharidosis (MPS-1)
286.0
Congenital factor VIII disorder (hemophilia A/VWF)
286.1
Congenital factor IX disorder([hemophilia B)
286.4
Von Willebrand’s disease
330.0
Leukodystrophy
333.4
Huntington’s chorea (Huntington's disease)
334.0
Friedreich’s ataxia (frataxin)
356.1
Peroneal muscular atrophy (Charcot-Marie-Tooth disease)
359.1
Hereditary progressive muscular dystrophy( [Duchene (dystrophin)] [Becker’s type] [limb girdle
muscular dystrophy (LGMD1, LGMD2)] [oculopharyngeal muscular dystrophy (OPMD)])
359.21359.29
742.2
753.10753.19
Myotonic disorders (myotonic dystrophy {CMPK, ZNF-9})
Reduction deformities of brain (classical lissencephaly)
Cystic kidney disease (including polycystic kidney, autosomal dominant)
756.4
Chondrodystrophy (achondroplasia)
756.51
Osteogenesis imperfecta
758.0
Down’s syndrome
758.31
Autosomal deletion syndromes; cri-du-chat syndrome
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758.32
Velo-cardio-facial syndrome [22q11 deletion syndrome (CATCH-22)]
758.6
Gonadal dysgenesis (ovarian dysgenesis, Turner's syndrome, XO syndrome)
758.7
Klinefelter’s syndrome
759.6
Other hamartoses, not elsewhere classified (Von Hippel Lindau syndrome)
759.81
Prader-Willi syndrome (GABRA, SNRPN)
V13.69
Personal history of other congenital malformations
V18.61
Family history of polycystic kidney disease
V77.3
Special screening for PKU
V77.7
Special screening for other inborn errors of metabolism
V83.01
Asymptomatic hemophilia A carrier
V83.02
Symptomatic hemophilia A carrier
Note: Molecular diagnostic testing (codes 83890-83914, 88384-88386) and cytogenetic studies (codes 88230-88291)
can be reported when there is no specific genetic testing CPT/HCPCS code. A genetic testing code modifier
specifying the probe type or the condition being tested can be appended to the CPT code to provide complete and
precise information regarding the genetic test being performed. See Table II in the Appendix for a list of modifiers
applicable to this policy.
ICD-10 codes are provided for your information. These will not become effective until 10/1/2014:
ICD-10
Code
Description
E34.3
Short stature due to endocrine disorder
E70.0
Classical phenylketonuria
E70.21
Tyrosinemia
E70.29
Other disorders of tyrosine metabolism
E70.30
Albinism, unspecified
E70.8
Other disorders of aromatic amino-acid metabolism
E71.0
Maple-syrup-urine disease
E71.120
Methylmalonic acidemia
E71.19
Other disorders of branched-chain amino-acid metabolism
E71.2
Disorder of branched-chain amino-acid metabolism, unspecified
E70.83
Other disorders of tyrosine metabolism
E72.10
Disorders of sulfur-bearing amino-acid metabolism, unspecified
E72.11
Homocystinuria
E72.12
Methylenetetrahydrofolate reductase deficiency
E72.19
Other disorders of sulfur-bearing amino-acid metabolism
E75.02
Tay-Sachs disease
E75.21
Fabry (-Anderson) disease
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E75.22
Gaucher disease
E75.249
Niemann-Pick disease, unspecified
E76.01
Hurler’s syndrome
E76.02
Hurler-Scheie
E76.03
Scheie’s syndrome
E76.1
Mucopolysaccharidosis, type II
E76.210
Morquio A mucopolysaccharidoses
E76.211
Morquio B mucopolysaccharidoses
E76.219
Morquio mucopolysaccharidoses, unspecified
E76.22
Sanfilippo mucopolysaccharidoses
E76.3
Other mucopolysaccharidoses
E76.3
Mucopolysaccharidosis, unspecified
D56.0
Alpha thalassemia
D56.1
Beta thalassemia
D57.00
Hb-SS disease with crisis, unspecified
D57.01
Hb-SS disease with acute chest syndrome
D57.02
Hb-SS disease with splenic sequestration
D57.1
Sickle-cell disease without crisis
D57.20
Sickle-cell/Hb-C disease without crisis
D57.211
Sickle-cell/Hb-C disease with acute chest syndrome
D57.212
Sickle-cell/Hb-C disease with splenic sequestration
D57.219
Sickle-cell/Hb-C disease with crisis, unspecified
D57.3
Sickle-cell trait
D57.40
Sickle-cell thalassemia without crisis
D66
Hereditary factor VIII deficiency
D67
Hereditary factor IX deficiency
D68.0
Von Willebrand’s disease
E75.23
Krabbe disease
E75.25
Metachromatic leukodystrophy
E75.29
Other sphingolipidosis
E77.0
Defects in post-translational modification of lysosomal enzymes
E77.1
Defects in glycoprotein degradation
E83.110
Hereditary hemochromatosis
E84.0
Cystic fibrosis with pulmonary manifestations
E84.19
Cystic fibrosis with other intestinal manifestations
E84.8
Cystic fibrosis with other manifestations
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E84.0
F70-F79
G10
Autistic disorder
Mental retardation, code range
Huntington’s disease
G11.1
Early-onset cerebellar ataxia
G12.9
Spinal muscular atrophy, unspecified
G60.0
Hereditary motor and sensory neuropathy
G71.0
Muscular dystrophy
G71.11
Myotonic muscular dystrophy
G71.12
Myotonia congenita
G71.13
Myotonic chondrodystrophy
G71.14
Drug induced myotonia
G71.19
Other specified myotonic disorders
I45.81
Long QT syndrome
K50.00
Crohn’s disease of small intestine without complications
K51.80
Other ulcerative colitis without complications
O26.20
Pregnancy care for patient with recurrent pregnancy loss, unspecified trimester
O26.21O26.23
Pregnancy care for patient with recurrent pregnancy loss (first, second, third trimester)
Q04.1
Arhinencephaly
Q04.2
Holoprosencephaly
Q04.3
Other reduction deformities of brain
Q55.4
Other congenital malformations of vas deferens, epididymis, seminal vesicles and prostate
Q61.19
Other polycystic kidney, infantile type
Q61.2
Polycystic kidney, adult type
Q77.1
Thanatophoric short stature
Q77.4
Achondroplasia
Q77.8
Other osteochondrodysplasia with defects of growth of tubular bones and spine
Q78.0
Osteogenesis imperfecta
Q85.01
Neurofibromatosis, type 1
Q85.02
Neurofibromatosis, type 2
Q85.8
Other phakomatoses, not elsewhere classified
Q87.1
Congenital malformation syndromes predominantly associated with short stature
Q93.4
Deletion of short arm of chromosome
Q93.81
Velo-cardio-facial syndrome
Q96.9
Turner’s syndrome, unspecified
Q98.4
Klinefelter syndrome, unspecified
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Q99.2
Fragile X chromosome
R62.0
Delayed milestone in childhood
Z13.220
Encounter for screening for lipoid disorders
Z13.228
Encounter for screening for other metabolic disorders
Z13.4
Encounter for screening for certain developmental disorders in childhood
Z13.89
Encounter for screening for other disorder
Z14.01
Asymptomatic hemophilia A carrier
Z14.02
Symptomatic hemophilia A carrier
Z14.1
Cystic fibrosis carrier
Z15.89
Genetic susceptibility to other disease
Z31.430
Encounter of female for testing for genetic disease carrier status for procreative management
Z31.440
Encounter of male for testing for genetic disease carrier status for procreative management
Z82.41
Family history of sudden cardiac death
Z86.71
Family history of polycystic kidney
Z82.79
Family history of other congenital malformations, deformations and chromosomal abnormalities
Z84.81
Family history of carrier of genetic disease
Z86.71
Personal history of venous thrombosis and embolism
Z87.798
Personal history of other (corrected) congenital malformations
V. Appendix
A. Table 1: LQTS Clinical Probability Score Card (i.e., Schwartz Score)
Finding
Points
History
Clinical history of syncope*
without stress
with stress
1
2
Congenital deafness
0.5
Family history of LQTS*
1
Unexplained sudden death in a first-degree family < 30 yrs. old*
0.5
ECG
Corrected QT interval (QTc by Bazett’s formula)
450 ms (in males)
460-470 ms
>480 ms
Torsade de pointes**
T-wave alternans
>3 Leads with notched T waves
Bradycardia (<second percentile for age)
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2
3
2
1
1
0.5
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B. Table II : Genetic code modifiers:
Modifier
Description
OC
Neurofibromin (Neurofibromatosis, type 1)
OD
Merlin (Neurofibromatosis, type 2)
OF
VHL (Von Hippel Lindau disease)
3A
F5 commonly called Factor V (Leiden, others) (Hypercoagulable state)
3D
HBB, beta globin (Thalassemia, Sickle cell anemia, other hemoglobinopathies)
3E
HBA, commonly called alpha globin (Thalassemia)
3F
MTHFR (Elevated homocystinemia)
3G
F2, commonly called prothrombin (20210, others)(Hypercoagulable state) Prothrombin (Factor II,
20210A)Hypercoagulable state
3H
F8, commonly called Factor VIII (Hemophilia A/VWF)
3I
F9, commonly called Factor IX (Hemophilia B)
3K
F13, commonly called Factor XIII (bleeding or hypercoagulable state) Beta globin
5A
ASPA, commonly called Aspartoacylase A (Canavan disease)
5B
FMR-1 (Fragile X, FRAXA, syndrome)
5C
FRDA commonly called Frataxin (Freidreich ataxia)
5D
HD commonly called Huntington (Huntington's disease)
5E
GABRA5, NIPA1, UBE3A, or ANCR GABRA (Prader Willi-Angelman syndrome)
5H
SNRPN (Prader Willi-Angelman syndrome)
5N
PMP-22(Charcot-Marie-Tooth disease, type 1A)
6A
DMD (Duchenne/Becker muscular dystrophy)
6B
DMPK (Myotonic dystrophy, type 1)
6C
ZNF-9 (Myotonic dystrophy, type 2)
6D
SMN1/SMN2 (Autosomal recessive spinal muscular atrophy)
7B
NPC1 or NPC2 (Nieman-Pick disease)
7C
GBA (Gaucher disease)
8A
CFRT (Cystic fibrosis)
8C
LQTS, KCN (Jervell and Lange-Nielsen syndromes, types 1, 2, 5, and 6) and SCN (Brugada
syndrome, SIDS and type 3)
9A
TPMT, Patients on antimetabolite therapy
9N
FGFR2 (Crouzon, Jackson-Weiss, Apert, Saethre-Chotzen syndromes)
9O
FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, types I and II, Crouzon
syndrome with acanthosis nigricans, Muencke syndromes)
9Q
DGCR, commonly
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VI. Policy History
Policy Number: M.DIA.04.121120
Current Effective Date: 12/01/2015
Original Document Effective Date: 11/20/2012
Previous Revision Dates: N/A
Scientific Background
This policy is based primarily on recommendations in the Final Report of the Task Force on Genetic Testing and the Secretary's
Advisory Committee on Genetic Testing. The Task Force on Genetic Testing was an official government advisory group reporting
to the National Advisory Council for Human Genome Research of the National Human Genome Research Institute, the National
Institutes of Health. The Secretary's Advisory Committee on Genetic Testing (SACGT) was established to advise the Department
of Health and Human Services on the medical, scientific, ethical, legal, and social issues raised by the development and use of
genetic tests.
Many genetic tests are imperfect predictors of either existing disease or disease susceptibility, particularly when used in the
context of population screening, where individuals without family histories of disease, risk factors or symptoms are tested. For
example, the probability exists that a disease may still occur, even when a negative test result is obtained. Conversely, a specific
disease may not occur when there is a positive test result. While these concepts hold true for at-risk individuals as well, the
probability of both these occurrences is greater in population screening, so test results are more difficult to interpret in a manner
that will meaningfully impact health outcomes. With a few limited exceptions (e.g., PKU testing), general screening of populations
for diseases that can be attributed to genetic mutations is not advocated in the published scientific literature.
Ideally, peer-reviewed literature on the performance and indications for the test should be available. The evaluation of a genetic
test focuses on these main principles: Analytic validity (technical accuracy of the test in detecting a mutation that is present or in
excluding a mutation that is absent); Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and
negative predictive values] in detecting clinical disease); and clinical utility (how results of the diagnostic test will be used to
change management of the patient and whether these changes in management lead to clinically important improvements in
health outcomes).
Analytical validity
Analytical validity is an indicator of how well a test measures the property or characteristic it is intended to measure, and it is
made up of three components Analytical sensitivity: the test is positive when the relevant gene mutation is present. Analytical
specificity: the test is negative when the gene mutation is absent and reliability: the test obtains the same result each time.
Clinical Validity
Clinical validity in genetic testing is a measurement of the accuracy with which a test identifies or predicts a clinical condition and
involves the following:
1. Clinical sensitivity: the probability that the test is positive if the individual being tested actually has the disease or a
predisposition to the disease.
2. Clinical specificity: the probability that the test is negative if the individual does not have the disease or a
predisposition to the disease.
3. Positive predictive value: the probability that an individual with positive test results will get the disease.
4. Negative predictive value: the probability that an individual with negative test results will not get the disease.
5. Heterogeneity: different mutations within the same gene may cause the same disease and can result in different
degrees of disease severity; a failure to detect all disease-related mutations reduces a test's clinical sensitivity.
6. Penetrance: the probability that the disease will appear when a disease-related genotype is present. Penetrance is
incomplete when other genetic or environmental factors must be present for a disease to develop.
The clinical utility of the test must be established.
Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy
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The development of genetic tests that can diagnose or predict disease occurrence has far outpaced the development of
interventions to treat, ameliorate or prevent those same diseases. Clinical utility refers to the ability of genetic test results, either
positive or negative, to provide information that is of value in the clinical setting. Specifically for positive test results, this could
involve instituting treatments or surveillance measures, making decisions concerning future conception, or avoiding harmful
treatments. Negative test results can have clinical utility in that unnecessary treatments or surveillance can be avoided. In the
absence of such interventions, the benefits of testing are limited, and in fact, can cause psychological harm.
Genetic testing of children to confirm current symptomatology or predict adult onset diseases is not considered medically
necessary unless direct medical benefit will accrue to the child and in the case of adult onset disease, this benefit would be lost
by waiting until the child has reached adulthood.
It is generally accepted in the published literature that unless useful medical intervention can be offered to children as a result of
testing, formal testing should wait until the child is old enough to understand the consequences of testing and request it for him
or herself. Ethical concerns related to the testing of children include the breach of confidentiality that is required by revealing test
results to parents, the lack of ability to counsel the child in a meaningful way regarding the risks and benefits of testing, the
impact a positive test could have in terms of discrimination, and the potential psychological damage that could occur from
distorting a family’s perception of the child.
Expanded Carrier Screening Panels
A 2011 study by Bell et al described the development of an ECS panel for 448 severe recessive diseases of childhood, using
next generation sequencing (NGS). The authors tested 104 unrelated DNA samples. They noted that although technical
standards and guidelines for laboratory-developed genetic testing for rare disorders in accredited laboratories have been
established, there are several challenges in their adoption for NGS and for bioinformatic-based testing of many conditions.
Specific national standards for quality assurance, quality control, test accessioning and reporting, and proficiency evaluation do
not currently exist. Also, issues of specificity and false positives are complex when hundreds of genes are being sequenced
simultaneously and need to be addressed.
Lazarin et al (2013) reported on carrier status from an ethnically diverse clinical sample of 23,452 individuals. Using the Counsyl
test screening platform, they assayed 417 disease-causing mutations associated with 108 recessive diseases. Of the individuals
tested, 5633 (24%) were heterozygous for at least 1 condition, and 5.2% were identified as carriers for multiple disorders. Of 127
carrier couples identified (ie, pairs of individuals identified as partners by self-report who were both found to share heterozygosity
for at least 1 disease), 47 (37%) were for alpha-1 antitrypsin deficiency, a condition Genetic Testing for Non-Cancerous
IInheritable Diseases 21 has reduced penetrance, variable severity, and uncertain clinical presentation in the newborn period
and into adulthood. The American Thoracic Society discourages genetic testing for alpha-1 antitrypsin deficiency in
asymptomatic adults with no increased risk for this disease.
In March 2011, six U.S. academic centers convened focus groups to examine genetics professionals’ views on ECS. Forty
genetics professionals, including those specializing in medical genetics, pediatric genetics, genetic counseling, public health
genetics, primary care, laboratory medicine, and law and bioethics, aimed to clarify how genetics professionals view potential
benefits and challenges of ECS. Overall, participants agreed that there was financial value in ECS panels compared with
conventional carrier screening. However, their findings highlighted major limitations of ECS. Concerns included the following:
 Use of ECS panels would be a significant departure from clinical practice guidelines in genetic and reproductive
healthcare in the U.S., and carrier screening guidelines currently exist for only a few of the genetic disorders evaluated
by ECS panels.
 Technical limitations of ECS include the inability to fully rule out the possibility of severe recessive diseases due to
rare mutations that could be identified by alternative methods such as DNA sequencing, and, there are gaps in
coverage of both specific genes and individual mutations included in the ECS panels.
 Current ECS panels typically examine only a fraction of the many genes associated with genetic disorders and limit
their evaluation to common genetic mutations within those genes.
 Reproductive healthcare providers might fail to recommend more conventional forms of targeted genetic evaluation,
such as screening tests indicated by a couple’s ethnicity, based on erroneous perceptions about the coverage of ECS
products being marketed as universal in scope. Less common mutations in specific ethnic populations may not be
included, and couples may be falsely reassured by “negative” results.
 As the number of individual assays on a multiplexed genetic test increases, the likelihood of erroneous results (eg,
false positives) and clinically ambiguous findings (eg, variants of unknown significance) increases significantly.
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 As carrier screening panels expand to include less common genetic diseases, interpretation of mutation results is
hindered by lack of data on clinical phenotypes associated with rare variants.
In 2013, Wienke et al issued a commentary on the limitations of using ECS panels. The authors stated that:
 Patients may not understand the nature of every disease on the panel, confounding the process of informed consent.
 In practice, it is infeasible to inform patients of the nature of each condition tested, and many healthcare providers are
unfamiliar with some of the conditions tested, making it difficult to communicate residual risk and action ability of
information obtained.
 It is possible that a test primarily designed to assess reproductive risk will inadvertently identify an asymptomatic
individual with the disease, which poses many challenges. These include unanticipated psychosocial burden to
patients, and a burden to the healthcare system in general as a person identified through this method may undergo
additional baseline testing for the disease and receive follow-up for the disease that may otherwise have been
unnecessary.
Genetic Testing for Non-Cancerous Inheritable Diseases Payment Policy
Policy number M.DIA.04.121120, effective 12/01/2015
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