Genetic Testing for Non-Cancerous Inheritable Diseases …€¦ · Genetic Testing for Non-Cancerous Inheritable ... no professional guidance as to which disease genes ... Genetic

Genetic Testing for Non-Cancerous Inheritable Diseases

Policy Number: Original Effective Date: MM.02.009 03/01/2010 Line(s) of Business: Current Effective Date: HMO; PPO; QUEST Integration 04/01/2015 Section: Medicine Place(s) of Service: Outpatient I. Description

A genetic test is the analysis of human DNA, RNA, chromosomes, proteins, or certain metabolites in order to detect alterations related to an inheritable disorder. This can be accomplished by directly examining the DNA or RNA that makes up a gene (direct testing), looking at markers co-inherited with a disease-causing gene (linkage testing), assaying certain metabolites (biochemical testing), or examining the chromosomes (cytogenetic testing). Genetic tests are conducted for a number of purposes, including predicting disease risk, newborn screening, determining clinical management, identifying carriers, and establishing prenatal or clinical diagnoses or prognoses in individuals, families, or populations.

Expanded Carrier Screening

The American College of Medical Genetics (ACMG ) defines expanded panels as those that use next-generation sequencing to screen for mutations in many genes, as opposed to gene-by-gene screening (e.g., ethnic-specific screening or panethnic testing for cystic fibrosis). An ACMG position statement states that although commercial laboratories offer expanded carrier screening panels, there has been no professional guidance as to which disease genes and mutations to include.

For the purpose of this policy, first-degree relatives are defined as parents, full siblings, and offspring. Second-degree relatives are defined as grandparents, grandchildren, aunts, uncles, nephews, nieces, half-siblings and third-degree relatives are defined as great-grandparents, great-aunts, great-uncles, first cousins.

This policy does not address oncology-related genetic testing or pre-implantation genetic diagnosis (PGD).

II. Criteria/Guidelines

A. Genetic testing for all the inheritable diseases listed below must meet the following factors (in addition to any specific criteria) in order to be covered:

Genetic Testing for Non-Cancerous Inheritable Diseases 2

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 for the conditions listed below 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 remain uncertain. These include but are not limited to:

Achrondroplasia

Amino acid metabolic disturbances

Charcot-Marie Tooth disease

Classical lissencephaly

Congenital hydrocephalus

Cri-du-chat

Cystic kidney disease (including polycystic kidney, autosomal dominant)

Down's syndrome

Dwarfism

Fabry disease

Factor XIII deficiency, congenital (Factor XIII beta globulin)

Friedreich's ataxia

Gonadal dysgenesis (Turner's, XO syndrome)

Hereditary progressive muscular dystrophy (Duchene[dystrophin]-Becker's type(limb girdle muscular dystrophy Oculopharyngeal muscular dystrophy

Neurofibromatosis type 2

Osteogenesis imperfecta

Phenylketonuria

Prader-Willi-Angelman syndrome

Peutz-jeghers

Thanatophoric dysplasia

Tuberous sclerosis

Turners syndrome

Velo cardio facial syndrome

Von Hippel-Lindau syndrome

Von Willebrand's disease

C. Preconceptional or prenatal genetic testing is covered (subject to Limitations/Exclusions and of Administrative Guidelines) for a parent or prospective parent to determine carrier status of cystic fibrosis according to the ACMG recommendations. The ACMG recommends testing for specific mutations which will result in a carrier detection rate of ≥95%. Ethnicities with the highest risk for cystic fibrosis are in the Caucasian and Ashkenazi Jewish populations.


D. The following genetic tests are covered (subject to Limitations/Exclusions and Administrative Guidelines) with precertification

1. Complete analysis of the cystic fibrosis transmembrane conductance regulator (CFTR) gene is covered (subject to Limitations/Exclusions and Administrative Guidelines) 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 mutation testing, using the

standard 23-mutation panel, has a negative result

2. Chromosomal microarray analysis for diagnosing a genetic abnormality in children with apparent nonsyndromic cognitive developmental delay /intellectual disability (DD/ID) or autism spectrum disorder (ASD) when ordered by a geneticist or pediatric neurologist when all of the following conditions are met:

a. Any indicated biochemical tests for metabolic disease have been performed, and results are non-diagnostic.

b. FMR1 gene analysis (for fragile X), when clinically indicated, is negative c. In addition to a diagnosis of nonsyndromic DD/ID or ASD, the child has one or more of the

following: i. Two or more major malformations, or ii. A single major malformation or multiple minor malformations, in an infant or child who

is also small-for-dates, or iii. A single major malformation and multiple minor malformations, and

d. The results from the genetic test have the potential to impact the clinical management of the patient

3. 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:

a. Individuals with a positive family history of SMA, limited to first- or second-degree relatives b. Reproductive partner of an individual with SMA or is a known SMA carrier c. Individuals with a first-degree relative identified as a SMA carrier

4. Genetic testing for 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:

a. Individuals with an intellectual disability, DD, or ASD b. Prenatal testing of fetuses of known carrier mothers c. Individuals planning a pregnancy who have either of the following;

i. A first- or second- degree relative with fragile X syndrome, or ii. A first- or second- degree relative with MR, etiology unknown

5. Carrier screening for Ashkenazi Jewish individuals for:

a. Tay-Sachs disease b. Canavan disease c. Familial Dysautomia


d. Fanconi anemia e. Niemann-Pick (type A) f. Bloom syndrome g. Gaucher disease

6. Genetic testing for HFE gene mutations related to hereditary hemochromatosis:

a. 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.

b. In individuals with a family history of hemochromatosis in a first degree relative.

7. Genetic testing for predisposition to hypertrophic cardiomyopathy (HCM) for individuals having one first-degree relative with established HCM when there is a known pathogenic gene mutation present in that affective relative.

8. 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:

a. A first- or second- degree relative with a known LQTS mutation b. A first- or second- degree relative diagnosed with LQTS by clinical means whose genetic

status is unavailable c. 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)

9. Genetic testing for Factor V Leiden and/or prothrombin G20210A mutations when any of the following criteria are met:

a. Age 50 or less , any venous thrombosis b. Age 50 or less , in patients who develop acute arterial thrombosis in the absence of other

risk factors for atherosclerotic arterial occlusive disease c. Venous thrombosis in unusual sites (such as portal hepatic, mesenteric and cerebral veins) d. Recurrent venous thrombosis e. Venous thrombosis and a first-or second- degree relative with thrombotic disease f. Venous thrombosis in pregnant women or women taking oral contraceptives g. Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental

abruption, intrauterine fetal growth retardation or stillbirth h. Myocardial infarction in female smokers under age 50

10. One-time genotypic or phenotypic analysis of the enzyme Thiopurine Methyltransferase (TPMT) is covered 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.

11. Genetic testing for hemoglobinopathies (i.e., thalassemias and sickle cell disease) is covered when one of the following criteria is met:

a. For confirmation of a diagnosis in either of the following situations:


i. For individuals with clinical features suggestive of a hemoglobinopathy when test results from conventional studies (e.g., Iron deficiency test and serum electrophoresis) are inconclusive and have failed a trial of iron therapy

ii. Infants who are diagnosed on newborn screening as having a hemoglobinopathy

b. For carrier testing in either of the following situations:

i. When there is an affected first- or second- degree relative with thalassemia or sickle cell disease

ii. 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

12. Because of the rapidly evolving field of genetic testing, this policy does not address every genetic test available. All other genetic tests not mentioned in this policy will be reviewed based on medical necessity and the policy criteria (II.A. 1-3).

III. Limitations/Exclusions

A. The following genetic tests are not covered because they have not been shown to improve health outcomes:

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. Genetic counseling is not a covered benefit.

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, HMSA 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.

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

IV. Administrative Guidelines

A. For the genetic tests requiring precertification. Complete HMSA's Precertification Request and fax or mail the form as indicated with 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

B. If precertification is not sought, the member will not be held responsible for payment of denied services unless an Agreement of Financial Responsibility is completed and signed.

C. Applicable codes requiring precertification:

CPT Description

81200 ASPA (aspartoacylase) (e.g. Canavan disease) gene analysis, common variants (e.g. E285A, Y231X)

81221 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis ;known familial variants

81222 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; duplication/deletion variants

81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; full gene sequence

81224 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis;; intron 8 poly-T analysis

81228 Cytogenetic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants, (e.g.,


Bacterial Artificial Chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis)

81229 Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number and single nucleotide polymorphism (SNP) variants for chromosomal abnormalities

81240 F2 (prothrombin, coagulation factor II) (e.g. hereditary hypercoagulability) gene analysis, 20210G>A variant

81241 F5 (coagulation factor V) (e.g. hereditary hypercoagulability) gene analysis, Leiden variant

81243 FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; evaluation to detect abnormal alleles

81244 FMR1 (fragile X mental retardation 1) (e.g. fragile X mental retardation) gene analysis; characterization of alleles

81251 GBA (glucosidase, beta, acid) (e.g., Gaucher disease) gene analysis, common variants (e.g., N370S, 84GG, l444P, IVS2+1G>A)

81255 HEXA (hexosaminidase A [alpha polypeptide]) (e.g., Tay-Sachs disease) gene analysis, common variants (e.g., 1278insTATC, 1421+1G>C, G269S)

81256 HFE (hemochromatosis) gene analysis, common variants (e.g., C282Y, H63D)

81257 HBA1/HBA2 (alpha globin 1 and alpha globin 2) (e.g., alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis, for common deletions or variant (e.g., Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and constant spring)

81260 Ikbkap (inhibitor of kappa light polypeptide gene enhancer in b-cells, kinase complex-associated protein) (eg, familial dysautonomia) gene analysis, common variants (eg, 2507+6t>c, r696p)

81280 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); full sequence analysis

81281 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); known familial sequence variant

81282 Long QT syndrome gene analyses (e.g., KCNQ1, KCNH2, SCN5A, KCNE1, KCNJ2, CACNA1C, CAV3, SCN4B, AKAP, SNTA1 and ANK2); duplication/deletion variants

81470 X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); genomic sequence analysis panel, must include sequencing of at


least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 (New 01-01-2015)

81471 X-linked intellectual disability (XLID) (eg, syndromic and non-syndromic XLID); duplication/deletion gene analysis, must include analysis of at least 60 genes, including ARX, ATRX, CDKL5, FGD1, FMR1, HUWE1, IL1RAPL, KDM5C, L1CAM, MECP2, MED12, MID1, OCRL, RPS6KA3, and SLC16A2 (New 01-01-2015)

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

S9870 Genetic analysis for a specific gene mutation for hypertrophic cardiomyopathy (HCM) in an individual with a known HCM mutation in the family

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)

299.00-299.01 Autistic disorder, current or active state or residual state

315.00-315.9 Specific delays in development code range

317-319 Intellectual disabilities code range

330.1 Cerebral lipidoses (Tay-Sachs disease)

335.10-335.19 Spinal muscular atrophy (SBMA,SMN)

425.11 Hypertrophic obstructive cardiomyopathy

426.82 Long QT syndrome

555.0-555.9 Regional enteritis, code range

556.0-556.9 Ulcerative colitis, code range


646.30 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)*

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)

V82.4 Maternal postnatal screening for chromosomal anomalies

* Definition from the American College of Obstetricians and Gynecologists: Practice Bulletin #24

D. Codes that do not require precertification:

CPT Description

81161 DMD (dystrophin) (eg, Duchenne/Becker muscular dystrophy) deletion analysis, and duplication analysis, if performed

81205 BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (e.g. Maple syrup urine disease) gene analysis, common variants (e.g. R183P, G278S, E422X)

81220 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g. cystic fibrosis) gene analysis; common variants

81290 MCOLN1 (mucolipin 1) (eg, mucolipidosis, type iv) gene analysis, common variants (eg, ivs3-2a>g, del6.4kb)

81324 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; duplication/deletion analysis

81325 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis; full sequence analysis

81326 PMP22 (peripheral myelin protein 22) (e.g., Charcot-Marie-Tooth, hereditary neuropathy with liability to pressure palsies) gene analysis ;known familial variant

81330 SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (e.g., Niemann-Pick disease, type A) gene analysis, common variants (e.g., R496L, L302P,


fsP330)

81331 SNRPN/UBE3A (small nuclear ribonucleoprotein polypeptide N and ubiquitin protein ligase E3A) (e.g., Prader-Willi syndrome and/or Angelman syndrome), methylation analysis

HCPCS 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 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)])

359.21 - 359.29 Myotonic disorders (myotonic dystrophy {CMPK, ZNF-9})


742.2 Reduction deformities of brain (classical lissencephaly)

753.10-753.19 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

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

V77.6 Screening for Cystic Fibrosis

V77.7 Special screening for other inborn errors of metabolism

V83.01 Asymptomatic hemophilia A carrier

V83.02 Symptomatic hemophilia A carrier

V83.81 Cystic fibrosis gene carrier

E. Codes that do not meet payment determination criteria

CPT Description

81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6) used in warfarin testing

81291 MTHFR (5, 10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)

81355 VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variants (eg, -1639/3673)

S3852 Dna analysis for apoe epsilon 4 allele for susceptibility to alzheimer's disease

Note: Molecular diagnostic testing (codes 83890-83914, 88384-88386) and cytogenetic studies (codes 88230-88291) can be reported prior to January 1, 2013 when there is no specific genetic testing CPT/HCPCS code.


ICD-10 codes are provided for your information. These will not become effective until the ICD-10 compliance date:

ICD-10 Description

Q85.01 Neurofibromatosis, type 1

Q85.02 Neurofibromatosis, type 2

E34.3 Short stature due to endocrine disorder

E70.0 Classical phenylketonuria

E70.1 Other hyperphenylalaninemias

E70.20 Disorder of tyrosine metabolism, unspecified

E70.21 Tyrosinemia

E70.29 Other disorders of tyrosine metabolism

E70.30 Albinism, unspecified

E70.310 X-linked ocular albinism

E70.311 Autosomal recessive ocular albinism

E70.318 Other ocular albinism

E70.319 Ocular albinism, unspecified

E70.320 Tyrosinase negative oculocutaneous albinism

E70.321 Tyrosinase positive oculocutaneous albinism

E70.328 Other oculocutaneous albinism

E70.329 Oculocutaneous albinism, unspecified

E70.330 Chediak-Higashi syndrome

E70.331 Hermansky-Pudlak syndrome

E70.338 Other albinism with hematologic abnormality

E70.339 Albinism with hematologic abnormality, unspecified

E70.39 Other specified albinism

E70.5 Disorders of tryptophan metabolism

E70.8 Other disorders of aromatic amino-acid metabolism

E70.9 Disorder of aromatic amino-acid metabolism, unspecified

E71.0 Maple-syrup-urine disease

E71.110 Isovaleric acidemia

E71.111 3-methylglutaconic aciduria

E71.118 Other branched-chain organic acidurias

E71.120 Methylmalonic acidemia

E71.121 Propionic acidemia

E71.128 Other disorders of propionate metabolism

E71.19 Other disorders of branched-chain amino-acid metabolism

E71.2 Disorder of branched-chain amino-acid metabolism, unspecified

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

E75.21 Fabry (-Anderson) disease

E75.22 Gaucher disease

E75.240 Niemann-Pick disease type A

E75.241 Niemann-Pick disease type B

E75.242 Niemann-Pick disease type C

E75.243 Niemann-Pick disease type D

E75.248 Other Niemann-Pick disease

E75.249 Niemann-Pick disease, unspecified

E75.3 Sphingolipidosis, unspecified

E77.0 Defects in post-translational modification of lysosomal enzymes

E77.1 Defects in glycoprotein degradation

E77.8 Other disorders of glycoprotein metabolism

E77.9 Disorder of glycoprotein metabolism, unspecified

E83.110 Hereditary hemochromatosis

E84.9 Cystic fibrosis, unspecified

E84.11 Meconium ileus in cystic fibrosis

E84.0 Cystic fibrosis with pulmonary manifestations

E84.19 Cystic fibrosis with other intestinal manifestations

E84.8 Cystic fibrosis with other manifestations

E76.01 Hurler's syndrome

E76.02 Hurler-Scheie syndrome

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

E76.29 Other mucopolysaccharidoses

E76.3 Mucopolysaccharidosis, unspecified

E76.8 Other disorders of glucosaminoglycan metabolism

E76.9 Glucosaminoglycan metabolism disorder, unspecified

D56.9 Thalassemia, unspecified

D57.40 Sickle-cell thalassemia without crisis

D57.411 Sickle-cell thalassemia with acute chest syndrome

D57.412 Sickle-cell thalassemia with splenic sequestration

D57.419 Sickle-cell thalassemia with crisis, unspecified

D56.0 Alpha thalassemia

D56.1 Beta thalassemia

D56.2 Delta-beta thalassemia


D56.3 Thalassemia minor

D56.5 Hemoglobin E-beta thalassemia

D56.8 Other thalassemias

D57.3 Sickle-cell trait

D57.1 Sickle-cell disease without crisis

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

D57.20 Sickle-cell/Hb-C disease without crisis

D56.4 Hereditary persistence of fetal hemoglobin [HPFH]

D58.2 Other hemoglobinopathies

D66 Hereditary factor VIII deficiency

D67 Hereditary factor IX deficiency

D68.0 Von Willebrand's disease

F84.0 Autistic disorder

F84.0 Autistic disorder

F70 Mild intellectual disabilities

F71 Moderate intellectual disabilities

F72 Severe intellectual disabilities

F73 Profound intellectual disabilities

F78 Other intellectual disabilities

F79 Unspecified intellectual disabilities

E75.23 Krabbe disease

E75.25 Metachromatic leukodystrophy

E75.29 Other sphingolipidosis

E75.00 GM2 gangliosidosis, unspecified

E75.01 Sandhoff disease

E75.02 Tay-Sachs disease

E75.09 Other GM2 gangliosidosis

E75.10 Unspecified gangliosidosis

E75.11 Mucolipidosis IV

E75.19 Other gangliosidosis

E75.4 Neuronal ceroid lipofuscinosis

G10 Huntington's disease

G11.1 Early-onset cerebellar ataxia

G12.9 Spinal muscular atrophy, unspecified

G12.1 Other inherited spinal muscular atrophy

G12.8 Other spinal muscular atrophies and related syndromes

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

I42.1 Obstructive hypertrophic cardiomyopathy

I45.81 Long QT syndrome

K50.00 Crohn's disease of small intestine without complications

K50.011 Crohn's disease of small intestine with rectal bleeding

K50.012 Crohn's disease of small intestine with intestinal obstruction

K50.013 Crohn's disease of small intestine with fistula

K50.014 Crohn's disease of small intestine with abscess

K50.018 Crohn's disease of small intestine with other complication

K50.019 Crohn's disease of small intestine with unspecified complications

K50.10 Crohn's disease of large intestine without complications

K50.111 Crohn's disease of large intestine with rectal bleeding

K50.112 Crohn's disease of large intestine with intestinal obstruction

K50.113 Crohn's disease of large intestine with fistula

K50.114 Crohn's disease of large intestine with abscess

K50.118 Crohn's disease of large intestine with other complication

K50.119 Crohn's disease of large intestine with unspecified complications

K50.80 Crohn's disease of both small and large intestine without complications

K50.811 Crohn's disease of both small and large intestine with rectal bleeding

K50.812 Crohn's disease of both small and large intestine with intestinal obstruction

K50.813 Crohn's disease of both small and large intestine with fistula

K50.814 Crohn's disease of both small and large intestine with abscess

K50.818 Crohn's disease of both small and large intestine with other complication

K50.819 Crohn's disease of both small and large intestine with unspecified complications

K50.90 Crohn's disease, unspecified, without complications

K50.911 Crohn's disease, unspecified, with rectal bleeding

K50.912 Crohn's disease, unspecified, with intestinal obstruction

K50.913 Crohn's disease, unspecified, with fistula

K50.914 Crohn's disease, unspecified, with abscess

K50.918 Crohn's disease, unspecified, with other complication

K50.919 Crohn's disease, unspecified, with unspecified complications

K51.80 Other ulcerative colitis without complications


K51.20 Ulcerative (chronic) proctitis without complications

K51.211 Ulcerative (chronic) proctitis with rectal bleeding

K51.212 Ulcerative (chronic) proctitis with intestinal obstruction


K51.213 Ulcerative (chronic) proctitis with fistula

K51.214 Ulcerative (chronic) proctitis with abscess

K51.218 Ulcerative (chronic) proctitis with other complication

K51.219 Ulcerative (chronic) proctitis with unspecified complications

K51.30 Ulcerative (chronic) rectosigmoiditis without complications

K51.311 Ulcerative (chronic) rectosigmoiditis with rectal bleeding

K51.312 Ulcerative (chronic) rectosigmoiditis with intestinal obstruction

K51.313 Ulcerative (chronic) rectosigmoiditis with fistula

K51.314 Ulcerative (chronic) rectosigmoiditis with abscess

K51.318 Ulcerative (chronic) rectosigmoiditis with other complication

K51.319 Ulcerative (chronic) rectosigmoiditis with unspecified complications

K51.40 Inflammatory polyps of colon without complications

K51.411 Inflammatory polyps of colon with rectal bleeding

K51.412 Inflammatory polyps of colon with intestinal obstruction

K51.413 Inflammatory polyps of colon with fistula

K51.414 Inflammatory polyps of colon with abscess

K51.418 Inflammatory polyps of colon with other complication

K51.419 Inflammatory polyps of colon with unspecified complications

K51.50 Left sided colitis without complications

K51.511 Left sided colitis with rectal bleeding

K51.512 Left sided colitis with intestinal obstruction

K51.513 Left sided colitis with fistula

K51.514 Left sided colitis with abscess

K51.518 Left sided colitis with other complication

K51.519 Left sided colitis with unspecified complications

K51.00 Ulcerative (chronic) pancolitis without complications

K51.011 Ulcerative (chronic) pancolitis with rectal bleeding

K51.012 Ulcerative (chronic) pancolitis with intestinal obstruction

K51.013 Ulcerative (chronic) pancolitis with fistula

K51.014 Ulcerative (chronic) pancolitis with abscess

K51.018 Ulcerative (chronic) pancolitis with other complication

K51.019 Ulcerative (chronic) pancolitis with unspecified complications


K51.811 Other ulcerative colitis with rectal bleeding

K51.812 Other ulcerative colitis with intestinal obstruction

K51.813 Other ulcerative colitis with fistula

K51.814 Other ulcerative colitis with abscess

K51.818 Other ulcerative colitis with other complication

K51.819 Other ulcerative colitis with unspecified complications

K51.90 Ulcerative colitis, unspecified, without complications

K51.911 Ulcerative colitis, unspecified with rectal bleeding


K51.912 Ulcerative colitis, unspecified with intestinal obstruction

K51.913 Ulcerative colitis, unspecified with fistula

K51.914 Ulcerative colitis, unspecified with abscess

K51.918 Ulcerative colitis, unspecified with other complication

K51.919 Ulcerative colitis, unspecified with unspecified complications

O26.20 Pregnancy care for patient with recurrent pregnancy loss, unspecified trimester

O26.21 Pregnancy care for patient with recurrent pregnancy loss, first trimester

O26.22 Pregnancy care for patient with recurrent pregnancy loss, second trimester

O26.23 Pregnancy care for patient with recurrent pregnancy loss, third trimester

Q04.0 Congenital malformations of corpus callosum

Q04.1 Arhinencephaly

Q04.2 Holoprosencephaly

Q04.3 Other reduction deformities of brain

Q61.00 Congenital renal cyst, unspecified

Q61.9 Cystic kidney disease, unspecified

Q61.01 Congenital single renal cyst

Q61.3 Polycystic kidney, unspecified

Q61.2 Polycystic kidney, adult type

Q61.11 Cystic dilatation of collecting ducts

Q61.19 Other polycystic kidney, infantile type

Q61.4 Renal dysplasia

Q61.5 Medullary cystic kidney

Q61.5 Medullary cystic kidney

Q61.02 Congenital multiple renal cysts

Q61.8 Other cystic kidney diseases

Q77.0 Achondrogenesis

Q77.1 Thanatophoric short stature

Q77.4 Achondroplasia

Q77.5 Diastrophic dysplasia

Q77.7 Spondyloepiphyseal dysplasia

Q77.8 Other osteochondrodysplasia with defects of growth of tubular bones and spine

Q77.9 Osteochondrodysplasia with defects of growth of tubular bones and spine, unspecified

Q78.4 Enchondromatosis

Q78.0 Osteogenesis imperfecta

Q90.0 Trisomy 21, nonmosaicism (meiotic nondisjunction)

Q90.1 Trisomy 21, mosaicism (mitotic nondisjunction)


Q90.2 Trisomy 21, translocation

Q90.9 Down syndrome, unspecified

Q93.4 Deletion of short arm of chromosome 5

Q93.81 Velo-cardio-facial syndrome

Q96.0 Karyotype 45, X

Q96.1 Karyotype 46, X iso (Xq)

Q96.2 Karyotype 46, X with abnormal sex chromosome, except iso (Xq)

Q96.3 Mosaicism, 45, X/46, XX or XY

Q96.4 Mosaicism, 45, X/other cell line(s) with abnormal sex chromosome

Q96.8 Other variants of Turner's syndrome

Q96.9 Turner's syndrome, unspecified

Q98.0 Klinefelter syndrome karyotype 47, XXY

Q98.1 Klinefelter syndrome, male with more than two X chromosomes

Q98.3 Other male with 46, XX karyotype

Q98.4 Klinefelter syndrome, unspecified

Q85.8 Other phakomatoses, not elsewhere classified

Q85.9 Phakomatosis, unspecified

Q87.1 Congenital malformation syndromes predominantly associated with short stature

Q99.2 Fragile X chromosome

R62.0 Delayed milestone in childhood

Z86.718 Personal history of other venous thrombosis and embolism

Z87.798 Personal history of other (corrected) congenital malformations

Z82.41 Family history of sudden cardiac death

Z82.71 Family history of polycystic kidney

Z13.228 Encounter for screening for other metabolic disorders

Z13.228 Encounter for screening for other metabolic disorders

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

V. 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.


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 which 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.

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 actionability 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.

VI. Important Reminder

The purpose of this Medical Policy is to provide a guide to coverage. This Medical Policy is not intended to dictate to providers how to practice medicine. Nothing in this Medical Policy is intended to discourage or prohibit providing other medical advice or treatment deemed appropriate by the treating physician.


Benefit determinations are subject to applicable member contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control.

This Medical Policy has been developed through consideration of the medical necessity criteria under Hawaii’s Patients’ Bill of Rights and Responsibilities Act (Hawaii Revised Statutes §432E-1.4), generally accepted standards of medical practice and review of medical literature and government approval status. HMSA has determined that services not covered under this Medical Policy will not be medically necessary under Hawaii law in most cases. If a treating physician disagrees with HMSA’s determination as to medical necessity in a given case, the physician may request that HMSA consider the application of this Medical Policy to the case at issue.

VII. References

1. Secretary's Advisory Committee on Genetic Testing. A public consultation on oversight of genetic tests. December 1, 1999 - January 31, 2000. National Institute of Health. Verified 10/25/2010

2. U.S. Preventive Services Task Force. Screening for hemochromatosis: Recommendation statement. Ann Intern Med. 2006 Aug 1;145(3):204-208

3. ACMG Policy Statement: Cystic fibrosis Population Carrier Screening: 2004 Revision of ACMG mutation panel. Reaffirmed 2013.

4. American College of Medical Genetic (ACMG) Practice Guidelines; Carrier screening for Spinal Muscular Atrophy. Genetics in Medicine 2008:10( 11) Reaffirmed 2013.

5. ACMG Practice Guidelines: Carrier screening in individuals of Ashkenazi descent. Genet Med 2008:10(1):54 –56. Reaffirmed 2013.

6. ACMG Practice Guidelines; Clinical genetics evaluation in identifying the etiology of autism spectrum disorders. 2013 Guideline Revisions

7. ACMG Practice Guidelines; Fragile X Syndrome: Diagnostic and carrier testing. October 2005 8. ACMG Consensus Statement on Factor V Leiden Mutation testing. Reaffirmed 05/14/2007 9. BCBSA Medical Policy Reference Manual. Pharmacogenetic and Metabolite Markers for Patients

Treated with Thiopurines #2.04.19. Last reviewed May 2014 10. ACMG Standards and Guidelines for Clinical Genetics Laboratories. Technical Standards and

Guidelines: Venous Thromboembolism (Factor V Leiden and Prothrombin 20210G>A Testing): A Disease-Specific Supplement to the Standards and Guidelines for Clinical Genetics Laboratories. 2006.

11. Bell CJ, Dinwiddie DL, Miller NA et al. Carrier testing for severe childhood recessive diseases by next generation sequencing. Sci Transl Med 2011; 3(65):65ra4.

12. BCBSA Medical Advisory Panel. Special Report: Evaluating evidence supporting a role for genetic markers assessing disease predisposition and prognosis, or predicting response to therapy. June 10, 2008

13. BCBSA Technology Evaluation Center Genetic testing for long QT syndrome. TEC Assessment 2007; volume 22 tab 9

14. American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics (ACMG). Preconception and Prenatal Carrier Screening for Cystic Fibrosis: Clinical and Laboratory Provider Guidelines. ACOG/ACMG Position Statement. ACOG; 2001

15. Genetic testing for HFE gene mutations related to hereditary hemochromatosis. BCBSA Technology Evaluation Center. Chicago, IL: April 2002; 16(22)


16. Special Report: Molecular karyotyping by array comparative genomic hybridization (aCGH) for the genetic evaluation of patients with developmental delay/mental retardation and autism spectrum disorder. BCBSA Medical Advisory Panel. December 2008

17. ACOG. Practice Bulletin #24. Testing guidelines for early recurrent pregnancy loss. 18. Wienke S, Brown K, Farmer M et al. Expanded carrier screening panels-does bigger mean better? J

Community Genet 2013. 19. BCBSA Medical Policy Reference Manual. Genetic Testing for Helicobacter pylori Treatment-

Archived. #2.04.50. Reviewed July 2012 Archived 20. Lazarin GA, Haque IS, Nazareth S et al. An empirical estimate of carrier frequencies for 400+ causal

Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med 2013; 15(3):178-86

21. BCBSA Medical Policy Reference Manual. Genetic Testing for Hereditary Hemochromatosis. #2.04.80. Reviewed April 2014

22. BCBSA Medical Policy Reference Manual. Chromosomal Microarray (CMA) Analysis for the Genetic Evaluation of Patients with Developmental Delay/Intellectual Disability or Autism Spectrum Disorder. #2.04.59. Reviewed March 2014

23. BCBSA Tec Assessment. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy. Vol. 34, No.11. August 2010

24. National Institute of Health. Genetics Home Reference. Sickle cell disease. Reviewed February 2007

25. BCBSA Medical Policy Reference Manual. Genetic Testing for FMR1 Mutations (Including Fragile X Syndrome). #2.04.83. Reviewed June 2014

26. BCBSA Medical Policy Reference Manual. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy. #2.02.28. Reviewed December 2013

27. Genetic Testing for Cystic Fibrosis. NIH Consensus Statement 1997 Apr 14-16; 15(4): 1-37. 28. ACMG Practice Guideline: Lack of Evidence for MTHFR Polymorphism Testing. Genet Med

2013:15(2):153–156 29. ACOG. Practice Bulletin #124. Inherited Thrombophilia in Pregnancy. September 11, 2011. 30. BCBSA Medical Policy Reference Manual. Carrier Testing for Genetic Diseases. #2.04.107. Last

reviewed: October 2014. 31. Grody WW, Thompson BH, Gregg AR et al. ACMG position statement on prenatal/preconception

expanded carrier screening. Genet Med 2013; 15(6):482-3.

VIII. Appendix

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 Family history of LQTS* Unexplained sudden death in a first-degree family < 30 yrs. old*

0.5 1 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)

1 2 3 2 1 1 0.5

A score <1 =low probability; 1 to <4 =intermediate probability; > 4=high probability. * Cannot count the same family member for both criteria ** Syncope and torsade de pointes are mutually exclusive

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