Genetic Testing for Neuromuscular Disorders (for Kentucky Only)

Coverage Summary

Policy CS165KY.07 (Genetic Testing for Neuromuscular Disorders — Kentucky only) is CURRENT and effective October 1, 2024. This policy addresses genetic testing for suspected neuromuscular disorders (NMDs) and defines coverage for multi-gene targeted panels. Multi-gene targeted panels that assess five or more genes (>=5) for the diagnosis of suspected NMDs (including congenital myopathy, distal myopathy, metabolic myopathy, myofibrillar myopathy, hereditary ataxia, hereditary peripheral neuropathy, hereditary spastic paraplegia, muscular dystrophy, and mitochondrial disease when specified criteria are met) are considered proven and medically necessary. In contrast, multi-gene comprehensive neuromuscular panels that target multiple conditions (for example, combined muscular dystrophy and mitochondrial disease panels) are considered unproven and not medically necessary.

Policy quick facts

Minimum genes in covered panelPanels must assess 5 or more genes (5+)

Covered disorder categoriesCongenital myopathy, distal/myofibrillar/metabolic myopathies; hereditary ataxia; hereditary peripheral neuropathy; hereditary spastic paraplegia; muscular dystrophy (eg, LGMD, congenital MD); mitochondrial disease (with mitochondrial-specific subcriteria)

Comprehensive multi-condition panelsMulti-gene panels that target multiple conditions (e.g., muscular dystrophy plus mitochondrial disease) are considered unproven and not medically necessary

Mitochondrial panel ordering requirementsMitochondrial testing must be ordered by or in consultation with a board-certified medical geneticist, developmental pediatrician, or neurologist and meet high clinical suspicion and other subcriteria

Effective date2024-10-01

Policy numberCS165KY.07

Medical Necessity Criteria

Not Medically Necessary / Unproven

Covered when ALL of the following are met:

ALL of the following

Suspected Neuromuscular Disorder includes ONE of
- Congenital myopathy, distal myopathy, metabolic myopathy (e.g., glycogen storage disease), or myofibrillar myopathy.
- Hereditary ataxia.
- Hereditary peripheral neuropathy.
- Hereditary spastic paraplegia.

Evidence Summary and Testing Strategy

This policy covers genetic test panels of five or more genes for neuromuscular disorders using technologies such as comparative genomic hybridization (CGH), next-generation sequencing (NGS), and sequencing approaches up to whole exome/genome testing. Panels can range from single-gene assays to large multi-gene panels and may include CNV analysis and targeted repeat expansion testing. Tests assist diagnosis, prognosis, and clinical management. Related UnitedHealthcare policies address genetic testing for cardiomyopathy-associated neuromuscular presentations (Genetic Testing for Cardiac Disease) and Whole Exome/Whole Genome Sequencing (WES/WGS), and the policy states that comprehensive multi-condition neuromuscular panels are unproven and not medically necessary.

Evidence and strategy summaries note that diagnostic yield for targeted NGS panels varies widely by condition, cohort selection, and panel design, with reported yields across studies ranging from low teens to over 50% depending on disorder and panel: examples include ataxia panels (~18–46%), IPN/CMT panels (~31–48% in some cohorts), and LGMD/myopathy panels (~19–53%). Inclusion of copy number variant (CNV) analysis and repeat expansion testing (for example, RFC1) increases diagnostic yield because sequence-only panels can miss deletions/duplications and repeat expansions. Several studies and guidelines recommend a phenotype-driven testing approach — using clinical evaluation, family history, imaging, electrodiagnostics, and targeted single-gene or small-panel testing where appropriate — before broad NGS; however, WES/WGS may be valuable and identify additional diagnoses when panels are negative or when phenotype is non-specific, and some studies report higher yields with WES after negative panels. Overall, the literature supports phenotype-directed testing first with incorporation of CNV and repeat analyses and use of WES/WGS as second-tier or in selected cases.

Study/Source	Reported diagnostic yield / key finding
Ebert et al. (2024)
77.1% positive (pathogenic mutation or VUS); 35.9% definitive diagnosis
Nemeth et al. (2013)
Overall detection rate 18%; 8.3% adult-onset progressive; 40% childhood/adolescent-onset
Ceylan et al. (2023)
39% positive by MLPA; 36% pathogenic/likely pathogenic among those with NGS panels; WES yield 80% in small subgroup
Lantern Project (Nallamilli et al., 2023)
19.6% molecular diagnosis across 6,473 cases; CNVs in 7.5% of positive cases
O'Grady et al. (2016)
48% overall genetic diagnosis using combination of targeted testing, NGS panels, and WES
Antoniadi et al. (2015)
31% genetic diagnosis (137/448) across 56 genes
Overall yield ranges (summary)
Reported diagnostic yields across cohorts/studies range approximately from ~10% to 77% depending on cohort, phenotype, panel design, and inclusion of CNV/repeat testing (examples in policy)

Coding

PLA / Proprietary Laboratory Analyses / Proprietary Codes referencedmixed

0216U	Neurology (inherited ataxias), genomic DNA sequence analysis of 12 common genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants.
0217U	Neurology (inherited ataxias), genomic DNA sequence analysis of 51 genes including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants.
0417U	Rare diseases (constitutional/heritable disorders), whole mitochondrial genome sequence with heteroplasmy detection and deletion analysis, nuclear-encoded mitochondrial gene analysis of 335 nuclear genes, including sequence changes, deletions, insertions, and copy number variants analysis, blood or saliva, identification and categorization of mitochondrial disorder-associated genetic variants.

Covered molecular CPT / Panel codes referencedCPTCovered

81440	Nuclear encoded mitochondrial genes panel, genomic sequence panel, must include analysis of at least 100 genes (examples listed).
81448	Hereditary peripheral neuropathies genomic sequence analysis panel, must include sequencing of at least 5 peripheral neuropathy-related genes.
81460	Whole mitochondrial genome genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection.
81465	Whole mitochondrial genome large deletion analysis panel, including heteroplasmy detection, if performed.
81479	Unlisted molecular pathology procedure.

Genes/targets explicitly recommended in guidelines and tiersmixed

PMP22	Duplication/deletion testing (CMT1A/HNPP)
GJB1 (Cx32)	GJB1 testing (X-linked CMT)
MFN2	MFN2 testing (axonal CMT)
MPZ	MPZ testing
EGR2	EGR2 testing
LITAF	LITAF testing
PRX	PRX testing
GDAP1	GDAP1 testing
RAB7	RAB7 testing
GARS	GARS testing

1–10 of 12

1/2

LGMD / MFM phenotype-directed genesmixed

DES	Desmin
MYOT	Myotilin
DNAJB6	DNAJB6
ZASP	ZASP (LDB3)
FLNC	Filamin C
CRYAB	Alpha-B crystallin
LMNA	Lamin A/C
CAV3	Caveolin-3
CAPN3	Calpain-3 (LGMD2A)
ANO5	ANO5 (LGMD2L)

1–10 of 15

1/2

Genes mentioned in cohort studies and panels (examples)mixed

SPG7	Associated with spastic paraplegia phenotype and ataxia
RFC1	Repeat expansion (CANVAS/RFC1)
MFN2, GJB1, MPZ, MME	Commonly identified in IPN cohorts
CAPN3, DYSF, GAA, ANO5, FKRP	Major contributors to LGMD in Lantern project
PABPN1, VCP, MYOT, LDB3, COL6A1, FLNC, DNAJB6	Other overlapping myopathy genes identified

Provider Actions & Requirements

Documentation Required

Mitochondrial testing specialist involvement

Mitochondrial testing must be ordered by or performed in consultation with a board-certified medical geneticist, developmental pediatrician, or neurologist. Documentation in the medical record must demonstrate a high degree of clinical suspicion for mitochondrial disease and explain why single-gene testing is not appropriate for the presenting phenotype.

Ordering clinician: board-certified medical geneticist, developmental pediatrician, or neurologist
Document rationale: why single-gene testing is not appropriate and evidence of high clinical suspicion

Billing Rule

Panel size requirement

Coverage applies to multi-gene targeted panels that assess five or more genes. Multi-condition panels that combine genes for distinct neuromuscular conditions (e.g., muscular dystrophy plus mitochondrial disease) are considered unproven and not medically necessary.

Definitions

Term	Definition
Comparative Genomic Hybridization (CGH)
Technology for detection of genomic copy number variations using labeled tumor and reference DNA hybridized on arrays; measures probe intensity differences.
Neuromuscular Disorders (NMD)
Inherited diseases causing impairment of nerves that control muscles or direct impairment of muscles.
Next Generation Sequencing (NGS)
High-throughput DNA sequencing of large numbers of genes in a single reaction.
Variant of Unknown Significance (VUS)
A genetic sequence variation with unknown association with disease.
Whole Exome Sequencing (WES)
DNA analysis technique that looks at all exons (protein-coding regions) in a person's DNA at once.
Whole Genome Sequencing (WGS)
Determines sequence of all nucleotides in a person's entire DNA including coding and non-coding elements.
NGS panel
Targeted next-generation sequencing assay evaluating a selected set of genes associated with a phenotype; may include CNV analysis and repeat testing depending on design.
CNV
Copy number variant — genomic deletions/duplications detectable by CNV analysis or MLPA/CGH.

Evidence Metrics

5+Minimum genes in covered panel

19.6%Lantern Project molecular diagnosis rate (6473 cases)

7.5%CNV contribution among Lantern positives

10%-77%Reported diagnostic yield range across studies (study-specific up to 77.1%)

OpenPayer