Clinical UM Guideline
Subject: Genetic Testing for Inherited Diseases
Guideline #: CG-GENE-13 Publish Date: 07/08/2020
Status: Reviewed Last Review Date: 05/14/2020
Description

This document addresses testing for certain diseases with an established genetic basis.  It includes testing of individual genes for individuals at risk and preconception or prenatal genetic testing of a prospective parent or parent to determine carrier status for an autosomal recessive disorder, an x-linked disorder, or a disorder with variable penetrance.

Notes:

Clinical Indications

Medically Necessary:

Testing of individual genes for inherited diseases is considered medically necessary when all the criteria for the individual to be tested and for the genetic disorder being tested for (both Criteria A and B) are met:

  1. Requirements for the individual:
    The individual to be tested:
    1. Is either at significant risk for a genetic disease (for example, based on family history) or suspected to have a known genetic disease; and
    2. Has received genetic counseling encompassing all of the following components:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
      4. Counseling for the psychological aspects of genetic testing.
        and
  2. Requirements for the genetic disorder(s) being tested for:
    1. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; and
    2. A biochemical or other test is identified but the results are indeterminate, or the genetic disorder cannot be identified through biochemical or other testing; and
    3. The genetic disorder is associated with a potentially significant disability or has a lethal natural history; and
    4. A positive or negative result of the genetic test will impact the clinical management (predictive, diagnostic, prognostic or therapeutic*) of the individual.  For example, genetic test results will guide treatment decisions, surveillance recommendations or preventive strategies; and
    5. The findings of the genetic test will likely result in improvement in net health outcomes; that is, the expected health benefits of the interventions outweigh any harmful effects (medical or psychological) of the intervention.

    *Note:  See the Definitions section for information about predictive, diagnostic, prognostic and therapeutic genetic testing.

    Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status of inherited disorders is considered medically necessary when criteria for family history and for the specific genetic test (both Criteria C and D) are met:
     
  3. Criteria based on family history:
    Genetic screening of the parent or prospective parent is considered medically necessary when one of the following criteria is met:
    1. An affected child is identified with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or
    2. One or both parents or prospective parent(s) have a first or a second degree relative who is affected with either an autosomal recessive disorder, an x-linked disorder, or an inherited disorder with variable penetrance and genetic testing is performed to determine the pattern of inheritance and to guide subsequent reproductive decisions; or
    3. The parent or prospective parent is at high risk for a genetic disorder with a late onset presentation, and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions; or
    4. The parent or prospective parent is a member of an ethnic group with a high risk of a specific genetic disorder with an autosomal recessive pattern of inheritance and genetic testing is performed to determine carrier status and to guide subsequent reproductive decisions, including but not limited to Tay-Sach’s disease, Canavan disease, familial dysautonomia, mucolipidosis IV, Niemann Pick Disease Type A, Fanconi anemia group C, Bloom syndrome or Gaucher disease.
      and
  4. Criteria for Specific Genetic Test:
    In the parent or prospective parent who meets one of the applicable criteria above, specific genetic testing is considered medically necessary when all of the following criteria are met:
    1. A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with the disease; and
    2. A biochemical or other test is identified but the results are indeterminate, or the genetic disorder cannot be identified through biochemical or other testing; and
    3. The genetic disorder is associated with a potentially severe disability or has a lethal natural history; and
    4. Genetic counseling, which encompasses all of the following components, has been performed:
      1. Interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
      2. Education about inheritance, genetic testing, disease management, prevention and resources; and
      3. Counseling to promote informed choices and adaptation to the risk or presence of a genetic condition;   and
      4. Counseling for the psychological aspects of genetic testing.

Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status for the following conditions is considered medically necessary:

  1. Cystic fibrosis, common variants (the current standard includes 23 of the more common gene mutations);
  2. Spinal muscular atrophy.

Not Medically Necessary:

Genetic testing of individual genes for inherited diseases in individuals not meeting the above criteria is considered not medically necessary, including, but not limited to, genetic testing for melanoma (hereditary), amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and ataxia telangiectasia.

Preconception or prenatal genetic testing of a parent or prospective parent for inherited medical disorders that do not meet the above criteria, including but not limited, to amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease) is considered not medically necessary.  

Preconception or prenatal genetic screening of a parent or prospective parent to determine carrier status for cystic fibrosis, using any of the following is considered not medically necessary:

  1. Complete DNA sequencing of the cystic fibrosis transmembrane conductance regulator (CFTR) gene;
  2. Gene analysis of known CFTR familial variants;
  3. Gene analysis of CFTR duplication/deletion variants.
Coding

The following codes for treatments and procedures applicable to this guideline are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

Cystic fibrosis and spinal muscular atrophy testing

Carrier testing:

CPT

 

81220

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; common variants (eg, ACMG/ACOG guidelines)

81329

SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; dosage/deletion analysis (eg, carrier testing), includes SMN2 (survival of motor neuron 2, centromeric) analysis, if performed

 

 

ICD-10 Diagnosis

 

 

All diagnoses (considered medically necessary)

Note: the following CFTR tests are considered not medically necessary for carrier testing:

CPT

 

81221

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; known familial variants

81222

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; duplication/deletion variants

81223

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; full gene sequence

 

 

ICD-10 Diagnosis

 

Z31.430

Encounter of female for testing for genetic disease carrier status for procreative management

Z31.440

Encounter of male for testing for genetic disease carrier status for procreative management

 

Note: for all other diagnoses, these tests may be medically necessary when criteria are met

Other CFTR and SMN1 testing:

CPT

 

 

Note: the following CFTR and SMN1 tests are considered medically necessary for preconception/prenatal diagnoses only:

81224

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, cystic fibrosis) gene analysis; intron 8 poly-T analysis (eg, male infertility)

81336

SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; full gene sequence

81337

SMN1 (survival of motor neuron 1, telomeric) (eg, spinal muscular atrophy) gene analysis; known familial sequence variant(s)

 

 

ICD-10 Diagnosis

 

 

All preconception/prenatal diagnoses including, but not limited to, the following:

Z31.430

Encounter of female for testing for genetic disease carrier status for procreative management

Z31.440

Encounter of male for testing for genetic disease carrier status for procreative management

Z36.0

Encounter for antenatal screening for chromosomal anomalies

Z36.8A

Encounter for antenatal screening for other genetic defects

Z84.81

Family history of carrier of genetic disease

 

Note: for all other diagnoses the CFTR and SMN1 tests listed above may be medically necessary when criteria are met

Other gene testing for inherited diseases for all indications:

CPT

 

81171

AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81172

AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; characterization of alleles (eg, expanded size and methylation status)

81187

CNBP (CCHC-type zinc finger nucleic acid binding protein) (eg, mytonic dystrophy type 2) gene analysis, evaluation to detect abnormal (eg, expanded alleles

81205

BCKDHB (branched-chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease) gene analysis, common variants (eg, R183P, G278S, E422X)

81209

BLM (Bloom syndrome, RecQ helicase-like) (eg, Bloom syndrome) gene analysis, 2281del6ins7 variant

81234

DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; evaluation to detect abnormal (expanded) alleles

81239

DMPK (DM1 protein kinase) (eg, myotonic dystrophy type 1) gene analysis; characterization of alleles (eg, expanded size)

81241

F5 (coagulation Factor V) (eg, hereditary hypercoagulability) gene analysis, Leiden variant

81242

FANCC (Fanconi anemia, complementation group C) (eg, Fanconi anemia, type C) gene analysis, common variant (eg, IVS4+4A>T)

81243

FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81244

FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and promoter methylation status)

81250

G6PC (glucose-6-phosphatase, catalytic subunit) (eg, Glycogen storage disease, Type 1a, von Gierke disease) gene analysis, common variants (eg, R83C, Q347X)

81251

GBA (glucosidase, beta, acid) (eg, Gaucher disease) gene analysis, common variants (eg, N370S, 84GG, L444P, IVS2+1G>A)

81256

HFE (hemochromatosis) (eg, hereditary hemochromatosis) gene analysis, common variants (eg, C282Y, H63D)

81257

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; common deletions or variant (eg, Southeast Asian, Thai, Filipino, Mediterranean, alpha3.7, alpha4.2, alpha20.5, and Constant Spring)

81258

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; known familial variant

81259

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; full gene sequence

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)

81269

HBA1/HBA2 (alpha globin 1 and alpha globin 2) (eg, alpha thalassemia, Hb Bart hydrops fetalis syndrome, HbH disease), gene analysis; duplication/deletion variants

81330

SMPD1(sphingomyelin phosphodiesterase 1, acid lysosomal) (eg, Niemann-Pick disease, Type A) gene analysis, common variants (eg, R496L, L302P, fsP330)

81361

HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); common variant(s) (eg, HbS, HbC, HbE)

81362

HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); known familial variant(s)

81363

HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); duplication/deletion variant(s)

81364

HBB (hemoglobin, subunit beta) (eg, sickle cell anemia, beta thalassemia, hemoglobinopathy); full gene sequence

81400

Molecular pathology procedure, Level 1 (eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) [when specified as the following]:

  • ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), K304E variant
  • BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (eg, maple syrup urine disease, type 1A), Y438N variant
  • F5 (coagulation factor V) (eg, hereditary hypercoagulability), HR2 variant

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [when specified as the following]:

  • ACADM (acyl-CoA dehydrogenase, C-4 to C-12 straight chain, MCAD) (eg, medium chain acyl dehydrogenase deficiency), commons variants (eg, K304E, Y42H)
  • GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), common variants (eg, Q188R, S135L, K285N, T138M, L195P, Y209C, IVS2-2A>G, P171S, del5kb, N314D, L218L/N314D)
  • PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), common variants (eg, R50S, G205S)

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]:

  • NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), duplication/deletion analysis
  • TTPA (tocopherol [alpha] transfer protein) (eg, ataxia), full gene sequence

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

  • ARSA (arylsulfatase A) (eg, arylsulfatase A deficiency), full gene sequence
  • BCKDHA (branched chain keto acid dehydrogenase E1, alpha polypeptide) (eg, maple syrup urine disease, type 1A), full gene sequence
  • DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease type 2), duplication/deletion analysis
  • DHCR7 (7-dehydrocholesterol reductase) (eg, Smith-Lemli-Opitz syndrome), full gene sequence
  • NLGN3 (neuroligin 3) (eg, autism spectrum disorders), full gene sequence;
  • NLGN4X (neuroligin 4, X-linked) (eg, autism spectrum disorders), full gene sequence
  • TGFBR1 (transforming growth factor, beta receptor 1) (eg, Marfan syndrome), full gene sequence
  • TGFBR2 (transforming growth factor, beta receptor 2) (eg, Marfan syndrome), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • ATP7B (ATPase, Cu++ transporting, beta polypeptide) (eg, Wilson disease), full gene sequence
  • BCKDHB (branched chain keto acid dehydrogenase E1, beta polypeptide) (eg, maple syrup urine disease, type 1B), full gene sequence
  • DBT (dihydrolipoamide branched chain transacylase E2) (eg, maple syrup urine disease, type 2), full gene sequence
  • DLD (dihydrolipoamide dehydrogenase) (eg, maple syrup urine disease, type III), full gene sequence
  • GAA (glucosidase, alpha; acid) (eg, glycogen storage disease type II [Pompe disease]), full gene sequence
  • GALT (galactose-1-phosphate uridylyltransferase) (eg, galactosemia), full gene sequence
  • PAH (phenylalanine hydroxylase) (eg, phenylketonuria), full gene sequence
  • PYGM (phosphorylase, glycogen, muscle) (eg, glycogen storage disease type V, McArdle disease), full gene sequence
  • RPE65 (retinal pigment epithelium-specific protein 65kDa) (eg, retinitis pigmentosa, Leber congenital amaurosis), full gene sequence
  • SLC37A4 (solute carrier family 37 [glucose-6-phosphate transporter], member 4) (eg, glycogen storage disease type Ib), full gene sequence

81408

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) [when specified as the following]:

  • MYH11 (myosin, heavy chain 11, smooth muscle) (eg, thoracic aortic aneurysms and aortic dissections), full gene sequence

81479

Unlisted molecular pathology procedure [for example: GBE1 (1,4-alpha-glucan branching enzyme 1) (eg. glycogen storage disease); ELP1 (elongator complex protein 1) (eg, familial dysautonomia)]

81599

Unlisted multianalyte assay with algorithmic analysis

0170U

Neurology (autism spectrum disorder [ASD]), RNA, next-generation sequencing, saliva, algorithmic analysis, and results reported as predictive probability of ASD diagnosis
Clarifi, Quadrant Biosciences, Inc, Quadrant Biosciences, Inc

 

 

HCPCS

 

S3845

Genetic testing for alpha-thalassemia

S3846

Genetic testing for hemoglobin E beta-thalassemia

S3849

Genetic testing for Niemann-Pick diseases

S3850

Genetic testing for sickle cell anemia

S3853

Genetic testing for myotonic muscular dystrophy

 

 

ICD-10 Diagnosis

 

 

All diagnoses

Other gene testing for preconception/prenatal testing

CPT

 

81173

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; full gene sequence

81174

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; known familial variant

81177

ATN1 (atrophin1) (eg, dentatorubral-pallidoluysian atrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81178

ATXN1 (ataxin 1) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81179

ATXN2 (ataxin 2) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81180

ATXN3 (ataxin 3) (eg, spinocerebellar ataxia, Machado-Joseph disease) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81181

ATXN7 (ataxin 7) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81182

ATXN8OS (ataxin 8 opposite strand [non-protein coding]) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81183

ATXN10 (ataxin 10) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81184

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81185

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; full gene sequence

81186

CACNA1A (calcium voltage-gated channel subunit alpha1 A) (eg, spinocerebellar ataxia) gene analysis; known familial variant

81188

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81189

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; full gene sequence

81190

CSTB (cystatin B) (eg, Unverricht-Lundborg disease) gene analysis; known familial variant(s)

81200

ASPA (aspartoacylase) (eg, Canavan disease) gene analysis, common variants (eg, E285A, Y231X)

81204

AR (androgen receptor) (eg, spinal and bulbar muscular atrophy, Kennedy disease, X chromosome inactivation) gene analysis; characterization of alleles (eg, expanded size or methylation status)

81252

GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; full gene sequence

81253

GJB2 (gap junction protein, beta 2, 26kDa, connexin 26) (eg, nonsyndromic hearing loss) gene analysis; known familial variants

81254

GJB2 (gap junction protein, beta 6, 30kDa, connexin 30) (eg, nonsyndromic hearing loss) gene analysis, common variants (eg, 309kb [del(GJB6-D13S1830)] and 232kb [del(GJB6-D13S1854)])

81255

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

81271

HTT (huntingtin) (eg, Huntington disease) gene analysis; evaluation to detect abnormal (eg, expanded) alleles

81274

HTT (huntingtin) (eg, Huntington disease) gene analysis; characterization of alleles (eg, expanded size)

81284

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; evaluation to detect abnormal (expanded) alleles

81285

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; characterization of alleles (eg, expanded size)

81286

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; full gene sequence

81289

FXN (frataxin) (eg, Friedreich ataxia) gene analysis; known familial variant(s)

81290

MCOLN1 (mucolipin 1) (eg, Mucolipidosis, type IV) gene analysis, common variants (eg, IVS3-2A>G, del6.4kb)

81302

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; full sequence analysis

81303

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; known familial variant

81304

MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants

81312

PABPN1 (poly[A] binding protein nuclear 1) (eg, oculopharyngeal muscular dystrophy) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81331

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

81333

TGFBI (transforming growth factor beta-induced) (eg, corneal dystrophy) gene analysis, common variants (eg, R124H, R124C, R124L, R555W, R555Q)

81343

PPP2R2B (protein phosphatase 2 regulatory subunit Bbeta) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81344

TBP (TATA box binding protein) (eg, spinocerebellar ataxia) gene analysis, evaluation to detect abnormal (eg, expanded) alleles

81402

Molecular pathology procedure, Level 3 (eg, > 10 SNP's 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD]) [when specified as the following]:

  • Uniparental disomy (UPD) (eg, Russell-Silver syndrome, Prader-Willi/Angelman syndrome), short tandem repeat (STR) analysis

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]:

  • KCNC3 (potassium voltage-gated channel, Shaw-related subfamily, member 3) (eg, spinocerebellar ataxia), targeted sequence analysis (eg, exon 2)

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

  • APTX (aprataxin) (eg, ataxia with oculomotor apraxia 1), full gene sequence
  • SIL1 (SIL1 homolog, endoplasmic reticulum chaperone [S. cerevisiae]) (eg, ataxia), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • AFG3L2 (AFG3 ATPase family gene 3-like 2 [S. cerevisiae]) (eg, spinocerebellar ataxia), full gene sequence
  • EIF2B5 (eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa) (eg, childhood ataxia with central nervous system hypomyelination/vanishing white matter), full gene sequence
  • HEXA (hexosaminidase A, alpha polypeptide) (eg, Tay-Sachs disease), full gene sequence
  • PRKCG (protein kinase C, gamma) (eg, spinocerebellar ataxia), full gene sequence
  • SETX (senataxin) (eg, ataxia), full gene sequence
  • UBE3A (ubiquitin protein ligase E3A) (eg, Angelman syndrome), full gene sequence

81407

Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) [when specified as the following]:

  • AGL (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) (eg, glycogen storage disease type III), full gene sequence

81408

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis)  [when specified as the following]:

  • ITPR1 (inositol 1,4,5-triphosphate receptor, type 1) (eg, spinocerebellar ataxia), full gene sequence

 

 

HCPCS

 

S3844

DNA analysis of the connexin 26 gene (GJB2) for susceptibility to congenital, profound deafness

 

 

ICD-10 Diagnosis

 

Z31.430

Encounter of female for testing for genetic disease carrier status for procreative management

Z31.440

Encounter of male for testing for genetic disease carrier status for procreative management

Z36.0

Encounter for antenatal screening for chromosomal anomalies

Z36.8A

Encounter for antenatal screening for other genetic defects

Z84.81

Family history of carrier of genetic disease

 

Note: for all other diagnoses, the tests listed above are considered not medically necessary

Other gene testing of individuals:

CPT

 

81332

SERPINA1 (serpin peptidase inhibitor, clade A, alpha-1 antiproteinase, antitrypsin, member 1) (eg, alpha-1-antitrypsin deficiency), gene analysis, common variants (eg, *S and *Z)

81401

Molecular pathology procedure, Level 2 (eg, 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) [when specified as the following]:

  • APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), common variants (eg, R3500Q, R3500W)

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

  • CPOX (coproporphyrinogen oxidase) (eg, hereditary coproporphyria), full gene sequence
  • LDLR (low density lipoprotein receptor) (eg, familial hypercholesterolemia), duplication/deletion analysis

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • HMBS (hydroxymethylbilane synthase) (eg, acute intermittent porphyria), full gene sequence
  • LDLR (low density lipoprotein receptor) (eg, familial hypercholesterolemia), full gene sequence
  • PCSK9 (proprotein convertase subtilisin/kexin type 9) (eg, familial hypercholesterolemia), full gene sequence
  • PPOX (protoporphyrinogen oxidase) (eg, variegate porphyria), full gene sequence

81407

Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) [when specified as the following]:

  • APOB (apolipoprotein B) (eg, familial hypercholesterolemia type B), full gene sequence

81479

Unlisted molecular pathology procedure [when specified as: LDLRAP1 (low density lipoprotein receptor adaptor protein 1) (eg. familial hypercholesterolemia)]

 

 

ICD-10 Diagnosis

 

 

Note: Gene tests listed above are considered not medically necessary for the following preconception/prenatal diagnoses:

Z31.430

Encounter of female for testing for genetic disease carrier status for procreative management

Z31.440

Encounter of male for testing for genetic disease carrier status for procreative management

Z36.0

Encounter for antenatal screening for chromosomal anomalies

Z36.8A

Encounter for antenatal screening for other genetic defects

Z84.81

Family history of carrier of genetic disease

Z31.430

Encounter of female for testing for genetic disease carrier status for procreative management

 

Note: for all other diagnoses the tests listed above may be medically necessary when criteria are met

Other not medically necessary testing

CPT

 

81403

Molecular pathology procedure, Level 4 (eg, analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) [when specified as the following]:

  • ANG (angiogenin, ribonuclease, RNase A family, 5) (eg, amyotrophic lateral sclerosis), full gene sequence

81404

Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) [when specified as the following]:

  • CDKN2A (cyclin-dependent kinase inhibitor 2A) (eg, CDKN2A-related cutaneous malignant melanoma, familial atypical mole-malignant melanoma syndrome), full gene sequence
  • SOD1 (superoxide dismutase 1, soluble) (eg, amyotrophic lateral sclerosis), full gene sequence

81405

Molecular pathology procedure, Level 6 (eg, analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) [when specified as the following]:

  • TARDBP (TAR DNA binding protein) (eg, amyotrophic lateral sclerosis), full gene sequence

81406

Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia) [when specified as the following]:

  • FUS (fused in sarcoma) (eg, amyotrophic lateral sclerosis), full gene sequence;
  • OPTN (optineurin) (eg, amyotrophic lateral sclerosis), full gene sequence

81407

Molecular pathology procedure, Level 8 (eg, analysis of 26-50 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of >50 exons, sequence analysis of multiple genes on one platform) [when specified as the following]:

  • SPTBN2 (spectrin, beta, nono-erythrocytic 2) (eg, spinocerebellar ataxia), full gene sequence

81408

Molecular pathology procedure, Level 9 (eg, analysis of >50 exons in a single gene by DNA sequence analysis) [when specified as the following]:

  • ATM (ataxia telangiectasia mutated) (eg, ataxia telangiectasia), full gene sequence

 

 

HCPCS

 

S3800

Genetic testing for amyotrophic lateral sclerosis (ALS)

 

 

ICD-10 Diagnosis

 

 

For all diagnoses the tests listed above are considered not medically necessary

Discussion/General Information

The phrase genetic testing can refer to the analysis of an individual’s deoxyribonucleic acid (DNA), ribonucleic acid (RNA), chromosomes, genes, or gene products, (such as enzymes and other proteins), to identify germline (inherited) or somatic (non-inherited) genetic variations associated with health or disease.  This document is only concerned with the testing of individual genes at the molecular level for individuals at risk or for preconception or prenatal testing.

The use of genetic testing information is being explored as a means to:

Genetic tests are done for many reasons:

Genetic Counseling
Due to the potential impact of positive genetic test results, it is generally recommended that genetic testing only be provided in conjunction with genetic counseling.  Genetic counseling should include a discussion of the potential risks for a particular genetic disorder and how identification of a genetic mutation will impact treatment management.  According to the National Society of Genetic Counselors (NSGC), genetic counseling is the process of assisting individuals to understand and adapt to the medical, psychological and familial ramifications of a genetic disease.  This process typically includes the guidance of a specially trained professional who:

  1. Integrates the interpretation of family and medical histories to assess the probability of disease occurrence or recurrence; and
  2. Provides education about inheritance, genetic testing, disease management, prevention and resources; and
  3. Provides counseling to promote informed choices and adaptation to the risk or presence of a genetic condition; and
  4. Provides counseling for the psychological aspects of genetic testing (NSGC, 2006).

The following table lists commonly requested gene testing targets, along with an assessment of whether or not they have been shown to be useful in guiding clinical management, determining carrier status, or guiding reproductive decisions. Tests listed in the table with a check in the column for, “Individual genome testing may impact clinical management” have been shown to be useful in guiding clinical management and, in the right circumstances, findings from genetic testing may result in improved net clinical outcomes.  There are many reasons why some of the tests below do not have a check mark.  This may be because knowledge of the genetic status does not change the management of the condition, has not been shown to facilitate decision making around reproduction, or may be associated with genes that exhibit problematic interpretation in the context of preconception or prenatal genetic testing (for example, conditions primarily associated with late age of onset, mild phenotype, and/or incomplete penetrance).

In addition to showing that a test may be useful for guiding clinical management, determining carrier status, or guiding reproductive decisions, requests for test coverage must also document that improvements in net health outcomes are expected as a result of the testing.

Gene

Condition

Preconception or prenatal genetic testing may be useful for determining carrier status and guiding reproductive decisions

Individual genome testing may impact clinical management

Additional Information

ACADM

Medium-chain acyl-coenzyme A dehydrogenase (MCAD)

ACOG # 690,
(2017, reaffirmed 2019)*

AFF2

Fragile X Syndrome

 

AFG3L2

Spinocerebellar ataxia Type 28 (SCA28)

 

 

AGL

Glycogen Storage Disease Type III

 

 

ANG

Amyotrophic lateral sclerosis

 

 

 

ApoB

Familial hypercholesterolemia  (principally APOB3500)

 

 

APTX

Ataxia with oculomotor apraxia Type 1

 

 

AR

Spinal and bulbar muscular atrophy (also known as Kennedy disease, X chromosome inactivation, X-linked spinal and bulbar muscular atrophy)

 

 

ARSA

Arylsulfatase A Deficiency

 

ASPA

Canavan disease

 

ACOG # 690,
(2017, reaffirmed 2019)*

ATM

Ataxia telangiectasia

 

 

 

ATN1 (DRPLA)

Dentatorubral-Pallidoluysian atrophy (also known as hereditary sensory and autonomic neuropathy type 1 with dementia and hearing loss, hereditary sensory neuropathy type IE, Haw River Syndrome, and Naito-Oyanagi disease)

 

 

ATP7B

Wilson disease (hepatolenticular degeneration)

 

ATXN1

Spinocerebellar ataxia type 1 (SCA1)

 

 

ATXN10

Spinocerebellar ataxia type 10 (SCA10)

 

 

ATXN2

Spinocerebellar ataxia type 2 (SCA2)

 

 

ATXN3

Spinocerebellar ataxia type 3 (SCA3)

 

 

ATXN7

Spinocerebellar ataxia type 7 (SCA7)

 

 

ATXN8

(ATXN8OS)

Spinocerebellar ataxia type 8 (SCA8)  

 

 

BCKDHA

Maple Syrup Urine Disease type 1A

ACOG # 690,
(2017, reaffirmed 2019)*

BCKDHB

Maple Syrup Urine Disease type 1B

ACOG # 690,
(2017, reaffirmed 2019)*

BLM

Bloom’s syndrome

ACOG # 690,
(2017, reaffirmed 2019)*

CACNA1A

Spinocerebellar ataxia type 6 (SCA6)

 

 

CDKN2A

Familial malignant melanoma

 

 

 

CFTR

Cystic fibrosis

ACOG # 690,
(2017, reaffirmed 2019)*

CNBP

Myotonic dystrophy type 2

 

CPOX

Hereditary coproporphyria

 

 

CSTB

Unverricht-Lundborg disease (ULD, EPM1)

 

 

DLD

Dihydrolipoamide dehydrogenase deficiency (E3-deficient maple syrup urine disease)

 

DBT

Maple Syrup Urine Disease type 2

 

DHCR7

Smith-Lemli-Opitz Syndrome (SLOS)

ACOG # 690,
(2017, reaffirmed 2019)*

DMPK

Myotonic dystrophy type 1

 

EIF2B5

Childhood ataxia with central nervous system hypomyelination/Vvanishing white matter

 

 

ELP1

Familial Dysautonomia

ACOG # 690,
(2017, reaffirmed 2019)*

F5

Factor V Leiden thrombophilia

 

FANCC

Fanconi anemia type C

ACOG # 690,
(2017, reaffirmed 2019)*

FMR1

Fragile X Syndrome

 

FUS

Amyotrophic lateral sclerosis

 

 

 

FXN

Friedreich ataxia (also known as Friedreich’s ataxia, FRDA)

 

 

G6PC

Glycogen storage disease type I (GSD I, Von Gierke disease)

 

GAA

Glycogen Storage Disease Type II (GSD II, Pompe disease)

 

GALT

Galactosemia

ACOG # 690,
(2017, reaffirmed 2019)*

GBA

Gaucher disease

ACOG # 690,
(2017, reaffirmed 2019)*

GBE1

Glycogen Storage Disease type IV

ACOG # 690,
(2017, reaffirmed 2019)*

GJB2

Nonsyndromic Hearing Loss and Deafness, (DFNB1)

 

 

HBA1

Alpha-thalassemia

 

HBA2

Alpha thallasemia

ACOG # 690,
(2017, reaffirmed 2019)*

HBB

Beta thalassemia

ACOG # 690,
(2017, reaffirmed 2019)*

HBB

Sickle cell disease

ACOG # 690,
(2017, reaffirmed 2019)*

HEXA

Tay-Sachs disease

 

ACOG # 690,
(2017, reaffirmed 2019)*

HFE

Hemachromatosis

 

HMBS

Acute intermittent porphyria

 

 

HTT

Huntington disease

 

 

IKBKAP

Familial dysautonomia

 

ITPR1

Spinocerebellar ataxia type 15 (SCA15)

 

 

KCNC3

Spinocerebellar ataxia type 13

 

 

LDLR

Familial hypercholesterolemia  (LDL) receptor (sometimes called the apoB/E receptor)

 

 

LDLRAP1

Familial hypercholesterolemia

 

 

MECP2

Rett syndrome

 

 

MCOLN1

Mucolipidosis

 

ACOG # 690,
(2017, reaffirmed 2019)*

MYH11

Marfan syndrome, Loeys-Dietz syndromes, and familial thoracic aortic aneurysms and dissections

 

NLGN3

Autism Spectrum

 

NLGN4X

Autism Spectrum

 

OPTN

Amyotrophic lateral sclerosis

 

 

 

PABPN1

Oculopharyngeal muscular dystrophy (also known as OPMD)

 

 

PAH

Phenylalanine hydroxylase deficiency

ACOG # 690,
(2017, reaffirmed 2019)*

PCSK9

Familial hypercholesterolemia  

 

 

PPOX

Variegate porphyria

 

 

PPP2R2B

Spinocerebellar ataxia type 12 (SCA12)

 

 

PRKCG

Spinocerebellar ataxia type 14 (SCA14)

 

 

PYGM

Glycogen storage disease type V GSD V)

 

RPE65

Hereditary retinal dystrophy

Also see MED.00120 Gene Therapy for Ocular Conditions

SERPINA1

Alpha-1 antitrypsin deficiency (AATD)

 

 

SETX

Ataxia with Oculomotor Apraxia Type 2

 

 

SIL1

Marinesco-Sjögren syndrome

 

 

SLC37A4

Glycogen Storage Disease type Ib

 

SMN-1

Spinal muscular atrophy

ACOG # 690,
(2017, reaffirmed 2019)*

SMPD1

Acid Sphingomyelinase Deficiency (Niemann-Pick disease type B)

ACOG # 690,
(2017, reaffirmed 2019)*

SNRPN

Prader-Willi syndrome

 

 

SOD1

Amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease)

 

 

 

SPTBN2

Spinocerebellar ataxia type 5 (SCA5)

 

 

 

TARDBP

Amyotrophic lateral sclerosis

 

 

 

TBP

Spinocerebellar ataxia type 17 (SCA17)

 

 

TGFBI

Corneal dystrophy

 

 

TGFBR1

Marfan syndrome, Loeys-Dietz syndromes, and familial thoracic aortic aneurysms and dissections

 

TGFBR2

Marfan syndrome, Loeys-Dietz syndromes, and familial thoracic aortic aneurysms and dissections

 

TTPA

Ataxia with vitamin E deficiency

 

UBE3A

Angelman syndrome

 

 

*American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017(a); 129(3):e35-e40. Reaffirmed 2019.

Preconception or Prenatal Testing

Carrier testing for inherited genetic conditions is a key component of preconception and prenatal care.  Carrier testing is conducted to identify an individual or a couple at risk (parent or prospective parent) for passing on genetic conditions to their offspring.  Carriers are asymptomatic individuals who are typically not at risk for developing the disease, but who possess the potential to pass the gene mutation to their offspring.  Carrier testing is frequently performed on the parent or prospective parent before conception or during a pregnancy.

Carrier screening may be conducted for conditions that are found in the general population (panethnic), for diseases that are more common in a particular population, or based on family history.  Panethnic screening (population screening) for carrier status is done for single-gene disorders that are common in the population.

Preconception or prenatal genetic testing of a parent or prospective parent is a common practice to determine carrier status.  For example, the American College of Obstetrics and Gynecology (ACOG) and the American College of Medical Genetics (ACMG) recommend carrier screening for:  Tay-Sach’s disease, Canavan disease, mucolipidosis IV, Niemann Pick Disease Type A, Fanconi anemia group C, Bloom syndrome, Gaucher’s disease and familial dysautonomia among individuals of Ashkenazi Jewish descent (ACOG, 2009; Gross, 2008).  With regard to Fragile X syndrome, the ACMG has provided guidance on prenatal and preconception testing, and ACOG has published a Committee Opinion for carrier screening (Sherman, 2005; ACOG, 2009; ACOG, 2010; ACOG, 2017[b]).

Amyotrophic Lateral Sclerosis and Other Adult-onset Diseases
There has also been a growing interest in the use of genetic testing for amyotrophic lateral sclerosis (ALS, Lou Gehrig’s disease).  ALS is an adult-onset, progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain that eventually results in paralysis and death. The mean age of onset for ALS is 56 years in individuals without a positive family history and 46 years in individuals with more than one affected family member (familial ALS).  Disease duration can vary significantly, but has been estimated to average approximately 3 years.  Death usually results from respiratory failure.  Alterations in several genes, including superoxide dismutase 1 (SOD1), angiogenin (ANG), TAR DNA binding protein (TARDP), and optineurin (OPTN), have been associated with the development of ALS.  Familial ALS can be inherited in an autosomal recessive, autosomal dominant, or X-linked fashion.  Penetrance of familial ALS is age and variant dependent; approximately 50% of individuals with an SOD1 pathogenic variant are symptomatic by 46 years of age and 90% are symptomatic by 70 years of age.  However, these percentages may be inflated due to ascertainment bias in families with high penetrance (Gene Reviews, 2015).

Neither ACOG nor ACMG recommend prenatal genetic testing for ALS.  With regard to predictive genetic testing and the screening of children for adult-onset conditions, the ACMG has indicated that, “If clinical benefits will not accrue for years to decades, testing should be deferred until adulthood or should require parent or guardian permission, as well as adolescent assent.”  ACMG also notes that most predictive genetic testing for adult-onset conditions is predispositional, that is, testing for genes that are incompletely penetrant and may never become manifest (Ross, 2013).  The ACOG Committee Opinion number 690 states, “Carrier screening panels should not include conditions primarily associated with a disease of adult onset” (ACOG, 2017[a]).  The National Society of Genetic Counselors (NSGC) does not support the use of prenatal genetic testing for known adult-onset conditions if pregnancy or childhood management will not be affected (Hercher, 2016).  Alpha 1 antitrypsin deficiency (incompletely associated with mutations in the SERPINA1 gene) provides another example of a condition with an adult-onset phenotype where molecular testing cannot distinguish between childhood or adult onset.  Likewise, preconception or prenatal genetic testing may not be appropriate for conditions, such as spinocerebellar ataxias (SCA) type 5 and familial malignant melanoma.  Mutations in the beta III spectrin gene (SPTBN2 gene) have been associated with spinocerebellar ataxias (SCA) type 5.  This is a relatively mild disorder that typically begins between the ages of 20 and 30 and progresses slowly.  CDKN2A, the most commonly identified gene mutation in familial forms of melanoma (adulthood age of onset), exhibits incomplete penetrance.

Cystic Fibrosis
Cystic fibrosis (CF) is a hereditary disease that affects many organs throughout the body and most of the exocrine glands.  As a result of the abnormal production of secretions, CF leads to organ and tissue damage, especially in the airways, liver, pancreas, intestines, sweat glands, and, in males, the vas deferens.  While several organs and tissues are affected by CF, pulmonary disease remains the predominant cause of morbidity and mortality in individuals with CF.  It has been estimated approximately 1 in every 31 Americans is an asymptomatic carrier of the defective CF gene. 

CF results when an individual inherits a gene mutation in both alleles of the CF transmembrane conductance regulator (CFTR) gene, located on chromosome 7q31.  The CFTR gene produces a protein that functions as a chloride channel and regulates bicarbonate and chloride transport, as well as other transport pathways.  More than 1900 different mutations in the CF gene have been identified.  The prevalence of carrier frequencies and mutation types varies among populations.  Non-Hispanic whites of Northern European descent have a carrier rate of 1 in 25 with the ΔF508 mutation being the most common.  It has been estimated that amongst individuals of Ashkenazi Jewish descent, CFTR mutation carrier frequency is 1 in 24.  When considered all together, the most common mutations in this population (W1282X, ΔF508, G542X, 3849+10kb C>T, and N1303K) account for at least 94% of the CF cases.

The clinical severity of CF symptoms is largely determined by the specific mutations that an individual carries.  Any individual who screens positive for CF should receive genetic counseling.  Negative screening results reduce, but do not totally eliminate, the possibility that the individual is a CF carrier.  A negative screening test only indicates that the individual does not carry any of the CF mutations specifically tested for during the screening. 

Due to the high prevalence of carriers of CF, ACOG and ACMG recommend that DNA screening for CF be made available to all individuals seeking preconception or prenatal care regardless of personal or family history for the disease or carrier status (ACOG, 2017[a], 2017[b]).  The National Society of Genetic Counselors (NSGC) recommends that carrier testing for CF be provided to women of reproductive age, regardless of ancestry.  The NSGC also recommends that prior to conception, “CF carrier testing should also be offered to any individual with a family history of CF and to partners of mutation carriers and people with CF” (Langfelder-Schwind, 2014).

Because so many different mutations in the CF gene have been identified, it is impractical to test for every known mutation.  In 2001, the ACMG Accreditation of Genetic Services Committee compiled a standard screening panel of 25 CF mutations to screen for CF in the U.S. population (Grody et al, 2001).  This 25-mutation test incorporated all CF-causing mutations with an allele frequency of greater than or equal to 0.1 % in the general U.S. population.  The test also included mutation subsets shown to be sufficiently predominant in certain ethnic groups, such as African Americans and Ashkenazi Jews.  The ACMG recommended that this standard panel of mutations be used to provide the greatest panethnic detectability that can be performed practically.  In the 2004 guidelines on CF Population Carrier Screening, the ACMG recommended using a panel that contains, at a minimum, 23 of the most common CF mutations (Watson, 2004).

According to the NSGC, carrier testing panels should include the mutations recommended by ACOG and ACMG.  For individuals of non-Northern European descent, panethnic panels that include additional mutations more commonly identified in minority populations are appropriate to consider.  NSGC also recommends that general population screening practices focus on, “Identifying carriers of established disease-causing CFTR mutations” (Langfelder-Schwind, 2014). 

In a recent Consensus Opinion, ACOG stipulated that:

Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening.  This type of testing generally is reserved for patients with cystic fibrosis, patients with negative carrier screening result but a family history of cystic fibrosis (especially if family test results are not available), males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing (using the standard 23-mutation panel) has a negative result.  Because carrier screening detects most mutations, sequence analysis should be considered only after discussion with a genetics professional to determine if it will add value to the standard screening that was performed previously (ACOG, 2017[b]).

Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a disease characterized by muscle atrophy and weakness caused by the progressive degeneration and loss of the brain stem nuclei and the anterior horn cells in the spinal cord, (that is, the lower motor neurons).  The onset of muscle weakness ranges from before birth to adolescence or young adulthood.  The weakness is symmetrical and progresses from proximal to distal.  Growth failure and poor weight gain, restrictive lung disease, scoliosis, joint contractures, and sleep difficulties are common complications (Prior, 2016).  The age of onset of symptoms roughly correlates with the extent to which motor function is affected with the earlier the age of onset, the more profound the impact on motor function.  Children who are symptomatic at birth or in infancy typically have the lowest level of function. 

SMA is caused by a mutation in the survival motor neuron gene (SMN1).  Due to the severity of the disease and the relatively high carrier frequency, there has been interest in carrier screening for SMA in the general prenatal population.  Because the genetics of SMA are complex and due to, “Limitations in the molecular diagnostic assays available, precise prediction of the phenotype in affected fetuses may not be possible” (ACOG, 2017[b]).

ACOG Committee Opinion No. 690 Carrier Screening in the Age of Genomic Medicine and No. 691 Carrier Screening for Genetic Conditions indicate that all individuals who are considering pregnancy or are already pregnant, regardless of screening strategy and ethnicity, should be offered carrier screening for SMA (ACOG 2017[a], ACOG 2017[b]).  The ACMG position statement on Carrier Screening for Spinal Muscular Atrophy also recommends panethnic screening for SMA (Prior, 2008).

Rett Syndrome
Rett syndrome is a disorder of the nervous system that leads to regression in development, especially in the areas of expressive language and hand use.  In most cases, it is caused by a genetic mutation on the X chromosome in the gene that contains instructions for creating methyl-CpG-binding protein 2 (MeCP2).  Rett syndrome occurs almost exclusively in girls and may be misdiagnosed as autism or cerebral palsy.  A child affected with Rett syndrome normally follows a standard developmental path for the first 5 months of life.  After that time, development in communication skills and motor movement in the hands seems to stagnate or regress.  After a short period, stereotyped hand movements, gait disturbances, and slowing of the rate of head growth become apparent.  Other problems may also be associated with Rett syndrome, including seizures, disorganized breathing patterns while awake and apraxia/dyspraxia (the inability to program the body to perform motor movements).  Apraxia/dyspraxia is a key symptom of Rett syndrome, and it results in significant functional impairment, interfering with body movement, including eye gaze and speech.

Definitions

Amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease): A progressive neurodegenerative disorder that affects nerve cells in the spinal cord and brain which eventually results in paralysis and death. 

Analytical validity: The accuracy with which a test identifies the presence or absence of a particular gene or genetic change (mutation).

Ashkenazi Jewish:  Persons related to Jewish settlers of the Rhine Valley in Germany and France in the middle ages.

Ataxia telangiectasia: A rare, progressive, neurodegenerative childhood disease that affects the brain and other body systems.

Carrier: An individual who is asymptomatic (or has only mild symptoms) of a disorder but has the potential to pass on the gene for that disorder to his or her offspring.

Clinical utility: Measures the ability of the test to improve clinical outcomes.

Clinical validity: The extent to which a test identifies or predicts an individual's clinical status.

Cystic fibrosis (CF): An inherited disease that affects the mucus and sweat glands of the body; thick mucus is formed in the breathing passages of the lungs that predisposes the person to chronic lung infections.

DNA: (deoxyribonucleic acid): A type of molecule that contains the code for genetic information.

Ethnicity: Coming from a large group that shares racial, national, language or cultural characteristics.

Exome: All the exons in a genome.

Exon: The portion of the genome that predominantly encodes protein.

Genetic molecular testing: A type of test that is used to determine the presence or absence of a specific gene or set of genes to help diagnose a disease, screen for specific health conditions, and for other purposes.

Genetic testing is done for predictive, diagnostic, prognostic or therapeutic indications as follows:

Genome: An organism's entire set of DNA.

Genotype: The genetic structure (constitution) of an organism or cell. 

Mutation:  A permanent change in the DNA code.

Next-generation sequencing: Any of the technologies that allow rapid sequencing of large numbers of segments of DNA, up to and including entire genomes.

Panethnic screening: A screening approach that is done for single-gene disorders based on ethnicity, race, or both.

Penetrant: The likelihood that a person carrying a particular variation of a gene will also have an associated trait.

Phenotype: The observable physical or biochemical characteristics of an organism, as determined by both genetic makeup and environmental influences.

Positive predictive value: Percentage of individuals with positive test results who are accurately diagnosed.

Rett syndrome: A developmental disorder that affects the parts of the brain that control social interaction, communications, and motor function.

Single-nucleotide polymorphisms (SNPs): DNA sequence variations that occur when a single nucleotide in the genome sequence is altered. 

References

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Government Agency, Medical Society, and Other Authoritative Publications:

  1. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14(8):759-761.
  2. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. 2009; 114(4):950-953. Reaffirmed 2014.
  3. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 469: Carrier screening for fragile X syndrome. Obstet Gynecol. 2010; 116(4):1008-1010.
  4. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol. 2011; 117(4):1028-1031. Reaffirmed 2014.
  5. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 690: Carrier screening in the age of genomic medicine. Obstet Gynecol. 2017(a); 129(3):e35-e40. Reaffirmed 2019.
  6. American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 691. Carrier screening for genetic conditions. Obstet Gynecol. 2017(b); 129(3):e41-e45.
  7. Andersen PM, Abrahams S, Borasio GD, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS)-revised report of an EFNS task force. Eur J Neurol. 2012; 19(3):360-375.
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  9. Blue Cross and Blue Shield Association. Sequencing for Clinical Diagnosis of Patients with Suspected Genetic Disorders. TEC Assessment, 2013; 28(3).
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  11. Burgunder JM, Schols L, Baets J, et al. EFNS guidelines for the molecular diagnosis of neurogenetic disorders: motoneuron, peripheral nerve and muscle disorders. Eur J Neurol. 2011; 18(2):207-217.
  12. Committee on Genetics and the Society for Maternal-Fetal Medicine. Microarrays and Next-Generation Sequencing Technology: The Use of Advanced Genetic Diagnostic Tools in Obstetrics and Gynecology. Obstet Gynecol. 2016; 128(6):e262-e268.
  13. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. 2015; 125(3):653-662.
  14. European Society of Human Genetics. Genetic testing in asymptomatic minors: Recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2009; 17(6):720-721.
  15. Genetic and Rare Diseases Information Center. Alpha-1 antitrypsin deficiency. Last updated September 26, 2018. Available at: https://rarediseases.info.nih.gov/diseases/5784/alpha-1-antitrypsin-deficiency. Accessed on April 8, 2020. 
  16. Green RC, Berg JS, Grody WW, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15(7):565-574.
  17. Gross SJ, Pletcher BA, Monaghan KG; et al. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. 2008; 10(1):54-56.
  18. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. 2001; 3(2):149-154.
  19. Grody WW, Griffin JH, Taylor AK, et al. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001; 3(2):139-148.
  20. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. 2013; 15(6):482-483.
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  24. Klintworth GK. Corneal dystrophies. Orphanet J Rare Dis. 2009; 4:7.
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  37. Stone EM, Aldave AJ, Drack AV, et al. Recommendations for genetic testing of inherited eye diseases: report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology. 2012; 119(11):2408-2410.
  38. Teutsch SM, Bradley LA, Palomaki GE, et al. The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group. Genet Med. 2009; 11(1):3-14.
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  40. U.S. Preventive Services Task Force. Screening for hemochromatosis: recommendation statement. Ann Intern Med. 2006; 145(3):204-208.
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  42. Yawn BP, John-Sowah J. Management of sickle cell disease: Recommendations from the 2014 Expert Panel Report. Am Fam Physician. 2015; 92(12):1069-1076. Available at: https://www.aafp.org/afp/2015/1215/p1069.html. Accessed on April 8, 2020.
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Websites for Additional Information
  1. American Board of Genetic Counselors. About genetic counseling. Available at: https://www.abgc.net/about-genetic-counseling/. Accessed on April 8, 2020.
  2. American College of Obstetricians and Gynecologists. Frequently asked questions. FAQ179. Pregnancy. Preconception Carrier Screening (2017). Available at: https://www.acog.org/~/media/For%20Patients/faq179.pdf. Accessed on April 8, 2020.
  3. National Library of Medicine (NLM). Genetics Home Reference. What are the types of genetic tests? Published March 12, 2019. Available at: https://ghr.nlm.nih.gov/primer/testing/uses. Accessed on April 8, 2020.
  4. National Library of Medicine (NLM). Genetic Conditions: Ataxia-telangiectasia. Reviewed January 2013. Published January 29, 2019. Available at: http://ghr.nlm.nih.gov/condition/ataxia-telangiectasia. Accessed on April 8, 2020.
Index

Bloom Syndrome
Canavan Disease
Counsyl Family Prep Screen
Cystic Fibrosis
Diagnostic genetic test
Fragile X syndrome
Rett syndrome
Pharmacotherapeutic genetic test
Predictive genetic test
Prognostic genetic test
Therapeutic genetic test
Fanconi Anemia Group C
Gaucher's Disease
Genetic Testing, Preconception or Prenatal
GoodStart GeneVu
Inherigen
Inheritest Carrier Screen
Mucolipidosis IV
Niemann Pick Disease Type A
Tay-Sach's Disease

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

History

Status

Date

Action

Reviewed

05/14/2020

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated table of genes to add: ApoB, LDLR, LDLRAP1, MYH11, PCSK9, TGFBR1, TGFBR2, HMBS, CPOX, PPOX. Updated Coding section to add these genes to the appropriate Tier 2 CPT codes; removed S3841, S3842 now addressed in CG-GENE-14.

 

04/01/2020

Updated Coding section with 04/01/2020 CPT changes; added 0170U.

 

02/27/2020

Updated formatting in Clinical Indications section.

New

11/07/2019

MPTAC review. Initial document development. Moved the contents of GENE.00012 Preconception or Prenatal Genetic Testing of a Parent or Prospective Parent and GENE.00043 Genetic Testing of an Individual’s Genome for Inherited Diseases into this new clinical UM guideline CG-GENE-13 Genetic Testing for Inherited Diseases with a new title. Removed the position statements about whole genome, whole exome and panel testing which were transitioned over to GENE.00052 Whole Genome Sequencing, Whole Exome Sequencing, Gene Panels and Molecular Profiling.  Revised Coding section to remove panel test codes 81410, 81411, 81415-81417, 81416, 81417, 81425-81427, 81430, 81431, 81440, 81442, 81443, 81460, 81465, 81470, 81471, 81506, 0012U, 0094U.

 


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