Genetic Testing for Non-Cancerous Inheritable Diseases - 11/13€¦ · • Fabry disease • Factor XIII (F13) deficiency, congenital ... • Von Willebrand's disease The following

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 11/01/2013 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.

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:

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).

Genetic Testing for Non-Cancerous Inheritable Diseases 2

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 (FGFR3) • Amino acid metabolic disturbances • Charcot-Marie Tooth disease (PMP-22) • Classical lissencephaly • Congenital hydrocephalus • Cri-du-chat • Cystic kidney disease (including polycystic kidney, autosomal dominant) • Down's syndrome • Dwarfism • Fabry disease • Factor XIII (F13) deficiency, congenital (Factor XIII beta globulin) • Friedreich's ataxia (FRDA [frataxin]) • Gonadal dysgenesis (Turner's, XO syndrome) • Hereditary progressive muscular dystrophy (Duchene[dystrophin]-Becker's type(limb girdle

muscular dystrophy [LGMD1, LGMD2])-Oculopharyngeal muscular dystrophy [OPMD])) • 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) • Von Willebrand's disease

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

C. Genetic testing for cystic fibrosis (CF) to determine carrier status in the following high-risk individuals:

1. Individuals with a positive family history of CF, limited to first- or second-degree relatives 2. Reproductive partner of an individual with CF or is a known carrier 3. Individuals with a first-degree relative identified as a CF carrier

D. 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:

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

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

3. If DD/ID or ASD is diagnosed in conjunction with phenotypic features consistent with a specific syndrome for which confirmatory testing cannot be accomplished by other cytogenetic methods (i.e., routine or high-resolution karyotype analysis fluorescence in situ hybridization)

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 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 mental retardation (MR), 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 MR, etiology unknown

G. Genetic testing for carrier status of Tay-Sachs, Canavan disease, Familial Dysautomia and Gaucher’s disease in individuals of Ashkenazi Jewish descent meeting the following high-risk indications:

1. A first-or second- degree relative with Tay-Sachs, Canavan disease, Familial Dysautomia, or Gaucher’s disease

2. Reproductive partner of an individual with Tay-Sachs, Canavan disease, Familial Dysautomia, or Gaucher’s disease or is a known Tay-Sachs, Canavan disease, Familial Dysautomia or Gaucher’s disease carrier

3. A first-degree relative identified as a Tay-Sachs, Canavan disease, Familial Dysautomia or Gaucher’s disease carrier

H. Genetic testing for HFE-associated hereditary hemochromatosis (HHC) gene mutations:

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 first-degree relative with established HCM.


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 50 or less , any venous thrombosis 2. Age 50 or less , in patients who develop acute arterial thrombosis in the absence of other risk

factors for atherosclerotic arterial occlusive disease 3. Venous thrombosis in unusual sites (such as portal hepatic, mesenteric and cerebral veins) 4. Recurrent venous thrombosis 5. Venous thrombosis and a first-or second- degree relative with thrombotic disease 6. Venous thrombosis in pregnant women or women taking oral contraceptives 7. Women with recurrent pregnancy loss or unexplained severe preeclampsia, placental

abruption, intrauterine fetal growth retardation or stillbirth 8. 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 individuals beginning therapy with azathioprine (AZA),mercaptopurine (6-MP) or thioguanine (6-TG) or in individuals 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 is met:

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

a. 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

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 with thalassemia or sickle cell disease

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 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. 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.

D. Laboratories that conduct genetic testing must be CLIA certified.

E. Genetic counseling is not a covered benefit.

F. Genetic tests for a specific inherited disease will be covered once per lifetime unless new techniques that increase sensitivity are utilized.

G. Home genetic testing is not a covered benefit.

H. 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).

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 for services rendered after January 1, 2013:

CPT Description

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

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

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

ICD-9 codes Description

272.7 Lipidoses

275.01 Hereditary hemochomatosis

277.00-277.09 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)

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

317-319 Mental retardation

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

V83.81 Cystic fibrosis gene carrier

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

D. Applicable codes for services rendered prior to January 1, 2013 requiring precertification:

HCPCS Description

S3845 Genetic testing for alpha-thalassemia

S3846 Genetic testing for hemoglobin E beta-thalassemia

S3850 Genetic testing for sickle cell anemia

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

E. Codes for services rendered after January 1, 2013 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)

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

S3853 Genetic testing for myotonic muscular dystrophy

F. Codes for services rendered prior to January 1, 2013:

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

V77.7 Special screening for other inborn errors of metabolism


V83.01 Asymptomatic hemophilia A carrier

V83.02 Symptomatic hemophilia A carrier

G. 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)

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 10/1/2014:

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 K51.80 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 K51.80 Other ulcerative colitis without 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.

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.

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. American College of Medical Genetic (ACMG) Practice Guidelines; Carrier screening for Spinal Muscular Atrophy. November 2008

4. ACMG Practice Guidelines; Carrier screening in individuals of Ashkenazi descent. November 2008 5. ACMG Practice Guidelines; Clinical genetics evaluation in identifying the etiology of autism

spectrum disorders. 2013 Guideline Revisions 6. ACMG Practice Guidelines; Fragile X Syndrome: Diagnostic and carrier testing. October 2005 7. ACMG Consensus Statement on Factor V Leiden Mutation testing. Reaffirmed 05/14/2007 8. BCBSA Medical Policy Reference Manual. Pharmacogenetic and Metabolite Markers for Patients

Treated with Thiopurines #2.04.19. Last reviewed June 2012 9. 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

10. 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

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

12. 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

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

14. 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

15. ACOG. Practice Bulletin #24. Testing guidelines for early recurrent pregnancy loss 16. BCBSA Medical Policy Reference Manual. Genetic Testing for Helicobacter pylori Treatment-

Archived. #2.04.50. Reviewed July 2012 Archived 17. BCBSA Medical Policy Reference Manual. Genetic Testing for Hereditary Hemochromatosis.

#2.04.80. Reviewed April 2013 18. 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 January 2013


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

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

21. BCBSA Medical Policy Reference Manual. Genetic Testing for FMR1 Mutations (Including Fragile X Syndrome). #2.04.83. Created June, 2012

22. BCBSA Medical Policy Reference Manual. Genetic Testing for Predisposition to Inherited Hypertrophic Cardiomyopathy. #2.02.28. Reviewed December 2012

23. Genetic Testing for Cystic Fibrosis. NIH Consensus Statement 1997 Apr 14-16; 15(4): 1-37. 24. ACMG Practice Guideline: Lack of Evidence for MTHFR Polymorphism Testing. Genet Med

2013:15(2):153–156 25. ACOG. Practice Bulletin #124. Inherited Thrombophilia in Pregnancy. September 11, 2011.

VIII. Appendix

Table 1 LQTS Clinical Probability Score Card (i.e., Schwartz Score)

Finding Points

History Clinical history of syncope*without stress

with stress

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

1 2 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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