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ModifiedAmbetter GeorgiaPolicy N/A

Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay — Coverage Criteria

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Defines medical necessity criteria and coding guidance for genetic testing (e.g., chromosomal microarray, gene-specific tests, panels, methylation and UPD analysis) used to evaluate multisystem inherited disorders, intellectual disability, developmental delay, and related conditions; applies to providers submitting claims to Ambetter Georgia/Coordinated Care as of the effective date.

Policy Summary

PayerAmbetter Georgia

PolicyGenetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay — Coverage Criteria

Policy CodePolicy N/A

Change TypeMultiple condition-specific revisions, code updates, and guideline incorporations

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionConfirm prior authorization and documentation meet the revised condition-specific clinical criteria before ordering or submitting claims.

SourceLink

POLICY UPDATE CHANGES

Policy language throughout was updated to replace 'coverage criteria' with 'criteria' and to modify condition-specific testing indications and code references (e.g., NF1 testing changes and code 81408 added as medically necessary in some contexts).

Specific guideline text and recommendations from specialty sources (Second International HHT Guidelines, AAP for NF1, International TSC Consensus) were incorporated into the document to support testing indications.

Multiple disorder-specific criteria were revised (NF1, NF2, Noonan/RASopathies, PIK3CA, TSC, CFTR, Angelman/Prader-Willi, Beckwith-Wiedemann/Russell-Silver) and coding/test lists updated.

Added coverage statement that CPT code 81408 is considered medically necessary for specified indications and added criterion that the member has at least specific clinical features for NF1 testing.

Removed several tests and codes from reference/test lists (examples: 81216, 81405, 81479, and certain exome example tests were removed or corrected).

Reworded and reorganized sections (e.g., Angelman/Prader-Willi criteria headers, CFTR criteria renamed to 'Diagnostic' to distinguish from carrier screening).

CMA recommendedCMA first-tier recommendation

81228,81229,S3870Example CMA CPTs

81408Newly added as necessary

81216,81405,81479Codes removed

>30References cited

Coverage Criteria and Condition-Specific Testing Indications

inv-01: Chromosomal Microarray — Medically Necessary Indications

Chromosomal microarray analysis for developmental delay, intellectual disability, autism spectrum disorder, or congenital anomalies is considered medically necessary in children when ANY one of the following is present:

CMA Indications: A. Global developmental delay and/or clinical diagnosis of intellectual disability (excluding isolated speech/language delay)

CMA Indications: B. Autism spectrum disorder

CMA Indications: C. Congenital anomalies

inv-02: Angelman/Prader-Willi — Medically Necessary Indications

SNRPN/UBE3A methylation analysis, 15q11-q13 FISH analysis, uniparental disomy (UPD) analysis, and imprinting center defect analysis to establish or confirm Angelman or Prader‑Willi syndrome are medically necessary when the syndrome‑specific clinical criteria below are met:

Policy Summary

PayerAmbetter Georgia

PolicyGenetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay — Coverage Criteria

Policy CodePolicy N/A

Change TypeMultiple condition-specific revisions, code updates, and guideline incorporations

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionConfirm prior authorization and documentation meet the revised condition-specific clinical criteria before ordering or submitting claims.

SourceLink

On This Page

Angelman syndrome criteria: Member has functionally severe developmental delay by age six to twelve months AND at least one characteristic clinical feature such as speech impairment with minimal words; movement or balance disorder; unique behaviors (frequent laughter/smiling, hand‑flapping); or significant dysmorphic features/congenital anomalies.

Prader‑Willi syndrome age‑specific criteria: Age‑specific combinations of hypotonia/poor suck, poor appetite with developmental delay (infancy), persistent hypotonia with developmental delay (toddler preschool), and later childhood/adolescent features including hyperphagia/excessive eating with central obesity and hypothalamic hypogonadism as detailed in policy.

inv-03: CMA - Medically Necessary vs Investigational

Chromosomal microarray analysis (CMA; e.g., 81228, 81229, S3870) is considered medically necessary in children when ANY one of the covered clinical indications is present and is investigational for other indications (including isolated speech/language delay):

CMA qualifying conditions: A. Global developmental delay and/or clinical diagnosis of intellectual disability (excluding isolated speech/language delay) OR B. Autism spectrum disorder OR C. Multiple congenital anomalies

CMA investigational: CMA is considered investigational for indications of delayed development that do not meet the listed criteria, including isolated speech/language delay.

inv-04: Angelman and Prader-Willi - Medically Necessary Criteria

Testing to diagnose or confirm Angelman or Prader‑Willi syndrome is considered medically necessary when the specific syndrome criteria and recommended testing sequence are met:

Required testing sequence: Begin with SNRPN/UBE3A methylation analysis (81331). If normal proceed to deletion analysis (e.g., 15q11‑q13 FISH); if deletion analysis is normal consider UPD analysis of chromosome 15 (81402); if UPD is normal consider imprinting center defect analysis.

Angelman medical necessity: Member meets Angelman criteria: functionally severe developmental delay by 6–12 months AND at least one characteristic clinical feature (speech impairment with minimal words; movement/balance disorder; characteristic behaviors) or significant dysmorphic features/congenital anomalies.

Prader‑Willi medical necessity: Member meets Prader‑Willi age‑specific criteria (neonatal hypotonia/poor suck; infancy hypotonia with poor appetite and developmental delay; toddler/preschool hypotonia with developmental delay; childhood with persistent hypotonia, global developmental delay, and hyperphagia/central obesity; adolescent/adult cognitive impairment with hyperphagia and hypothalamic hypogonadism).

inv-05: Beckwith-Wiedemann and Russell-Silver - Medically Necessary Criteria

Beckwith‑Wiedemann and Russell‑Silver syndrome testing (methylation, deletion/duplication, UPD, CDKN1C analysis) is medically necessary when the clinical feature thresholds below are met:

Beckwith‑Wiedemann (BWS): Member has at least one Tier‑1 or Tier‑2 clinical feature (examples include macroglossia; abdominal wall defect requiring surgery; embryonal tumor such as Wilms tumor; hemihyperplasia; macrosomia [>90th or >97th centile]; hyperinsulinemic hypoglycemia; visceromegaly; characteristic facies; kidney anomalies; transient hypoglycemia; or positive family history).

Russell‑Silver syndrome (SRS): Member meets at least three Netchine‑Harbison clinical scoring system (NH‑CSS) features (e.g., small for gestational age, postnatal growth failure, relative macrocephaly, frontal bossing, body asymmetry, feeding difficulties) — molecular confirmation indicated when 4 of 6 are met and considered in select cases with 3 of 6.

inv-06: Cystic Fibrosis - Medically Necessary Criteria

Diagnostic CFTR sequencing and/or deletion/duplication and intron poly‑T/TG analysis are medically necessary when any of the following diagnostic triggers are present:

CFTR diagnostic triggers: A. Positive (>=60 mmol/L) or inconclusive (30–59 mmol/L) sweat chloride test, OR B. Positive newborn screen for CF (elevated IRT), OR C. Symptoms involving at least TWO organ systems consistent with CF (sinus, lower respiratory, GI/lumen, GI/hepatobiliary, reproductive, or other characteristic features).

Intron poly‑T/TG reflex: CFTR intron 9 polyT/TG analysis (81224) is medically necessary when the member has a diagnosis of cystic fibrosis and an R117H variant; ACMG recommends reflex testing for 5T/7T/9T when R117H is detected.

inv-07: CHARGE - Medically Necessary Criteria

CHD7 sequencing and/or deletion/duplication analysis is medically necessary when the member has at least two characteristic CHARGE features:

CHARGE criteria: Member has two or more features such as coloboma; anophthalmos/microphthalmos; choanal atresia/stenosis; cleft palate; cranial nerve dysfunction (e.g., hyposmia/anosmia, facial palsy, sensorineural hearing loss); ear malformations; tracheoesophageal fistula; cardiovascular malformation; hypogonadotropic hypogonadism; developmental delay; growth deficiency; characteristic facial/hand features; or supportive brain MRI findings.

inv-08: Fanconi Anemia - Medically Necessary Criteria

A Fanconi anemia multigene panel is medically necessary when ALL of the following are met:

Fanconi anemia panel criteria: A. Prior positive or inconclusive chromosome breakage analysis AND B. The member displays at least one suggestive clinical or laboratory feature (e.g., short stature; abnormal skin pigmentation; skeletal malformations such as hypoplastic thumb; microcephaly; ophthalmic anomalies; genitourinary anomalies; macrocytosis; increased fetal hemoglobin; cytopenias; progressive bone marrow failure; early‑onset malignancy or inordinate chemo/radiation toxicity).

inv-09: Fragile X - Medically Necessary Criteria

Diagnostic FMR1 repeat and methylation analysis is medically necessary when any of the following clinical situations are present:

Fragile X indications: Unexplained intellectual disability or developmental delay (male or female), males with unexplained autism, females with autism and features compatible with Fragile X or a close relative with X‑linked neurodevelopmental disorder, primary ovarian insufficiency before age 40, or progressive intention tremor and cerebellar ataxia (age >=50) of unknown cause.

inv-10: Hereditary Hemorrhagic Telangiectasia - Medically Necessary Criteria

HHT multigene panel analysis (panel must include at minimum ACVRL1 and ENG) is medically necessary when guideline‑based clinical indications are met:

HHT panel criteria: A. Member has characteristic clinical features such as spontaneous/recurrent epistaxis, mucocutaneous telangiectases at characteristic sites, or visceral AVMs OR a first‑degree relative meeting Curaçao criteria; AND B. The multigene panel includes at minimum ACVRL1 and ENG (consider SMAD4 if ENG/ACVRL1 negative).

HHT testing use cases: Use diagnostic testing to identify a causative family mutation, to test at‑risk relatives (including asymptomatic individuals or those desiring prenatal testing), or to assist diagnosis in individuals who do not meet full clinical criteria.

inv-11: Neurofibromatosis 1 - Medically Necessary Criteria

NF1 sequencing and/or deletion/duplication analysis (81408) is medically necessary when the member has at least one of the listed NIH diagnostic features or a biological parent who meets diagnostic criteria:

NF1 indications: Six or more café‑au‑lait macules (size thresholds defined), two or more neurofibromas or one plexiform neurofibroma, axillary/inguinal freckling, optic glioma, two or more Lisch nodules, a distinctive osseous lesion (e.g., sphenoid dysplasia or tibial pseudarthrosis), OR a biological parent meeting diagnostic criteria.

NF1 clinical rationale: Genetic testing may be performed to confirm suspected NF1 in young children presenting only with café‑au‑lait macules, to differentiate from Legius syndrome, or for atypical presentations; sensitivity ~95%.

inv-12: NF2-related Schwannomatosis - Medically Necessary Criteria

NF2 sequencing and/or deletion/duplication analysis is medically necessary when specific tumor or clinical feature combinations are present (adult or pediatric criteria):

NF2 adult indications: Pathogenic NF2 variant identified on tumor tissue testing; OR adult with bilateral vestibular schwannomas; OR unilateral vestibular schwannoma plus >=2 other tumor types (meningioma, schwannoma, glioma, neurofibroma, cataract) ; OR adult with multiple meningiomas plus associated features.

NF2 pediatric indications: Child with at least two of schwannoma (any location), skin plaques present at birth/early childhood, meningioma, cortical wedge cataract, retinal hamartoma, or a mononeuropathy (e.g., facial palsy, foot/wrist drop).

inv-13: Noonan Spectrum Disorders / RASopathies - Medically Necessary Criteria

A Noonan spectrum disorders / RASopathy multigene panel (81442) is medically necessary when the member has at least one characteristic clinical feature:

Noonan/RASopathy indications: Characteristic facies; short stature; congenital heart defect (e.g., pulmonary valve stenosis, hypertrophic cardiomyopathy); developmental delay; broad/webbed neck; unusual chest shape; widely spaced nipples; cryptorchidism; lentigines; or café‑au‑lait macules.

Sequential testing note: Given ~50% detection rate of PTPN11 variants in Noonan syndrome, single‑gene PTPN11 testing may be an appropriate initial test in some presentations before broader panel testing.

inv-14: PIK3CA-Related Segmental Overgrowth - Medically Necessary Criteria

PIK3CA sequencing analysis (81479) to establish a diagnosis of PIK3CA‑Related Segmental Overgrowth is medically necessary when ALL of the following are met:

PIK3CA medical necessity: I. At least one qualifying brain imaging finding (hemimegalencephaly, focal cortical dysplasia, or dysplastic megalencephaly) AND II. At least one early‑onset overgrowth or related clinical feature (congenital/early‑childhood overgrowth of tissues; vascular malformations; lymphatic malformations; cutaneous findings such as epidermal nevi or hyperpigmented macules; digital anomalies e.g., macrodactyly; kidney malformations; or benign tumors excluding Wilms/nephroblastomatosis).

PIK3CA mosaicism note: Because the majority of pathogenic PIK3CA variants are mosaic, more than one tissue type (e.g., blood, skin, saliva) may need testing; a negative test does not exclude the diagnosis.

inv-15: PIK3CA-Related Segmental Overgrowth — medically necessary criteria

PIK3CA sequencing analysis is considered medically necessary to establish a diagnosis of PIK3CA‑Related Segmental Overgrowth when ALL of the following are present; it is investigational for other indications:

PIK3CA_medical_necessity: I. Brain imaging showing at least one of: hemimegalencephaly, focal cortical dysplasia, or dysplastic megalencephaly; AND II. Presence from birth or early childhood of at least one of the listed clinical features (overgrowth of tissues, vascular malformations, lymphatic malformations, cutaneous findings, digital anomalies, kidney malformations, or benign tumors excluding Wilms/nephroblastomatosis).

PIK3CA_investigational: PIK3CA sequencing analysis (81479) is investigational for all other indications outside those specified above.

inv-16: PIK3CA — investigational uses

PIK3CA sequencing analysis (81479) is considered investigational when performed for indications other than establishing a diagnosis of PIK3CA‑Related Segmental Overgrowth per the policy criteria.

PIK3CA investigational uses: PIK3CA sequencing analysis is investigational for all indications not meeting the policy's specified imaging and clinical feature criteria.

inv-17: Tuberous Sclerosis Complex — medically necessary criteria

TSC1 and TSC2 sequencing and/or deletion/duplication analysis is medically necessary to establish or confirm Tuberous Sclerosis Complex when the following diagnostic genetic/clinical criteria are met:

TSC genetic or clinical diagnosis: Identification of a pathogenic variant in TSC1 or TSC2 is sufficient for diagnosis and is medically necessary for genetic counseling or when TSC is suspected; OR testing is medically necessary when the member has at least one major feature OR at least two minor features as listed in the policy.

TSC major/minor features: Major features include angiofibromas (>3) or fibrous cephalic plaque; cardiac rhabdomyoma; multiple cortical tubers/radial migration lines; hypomelanotic macules (>=3 of 5 mm); LAM; multiple retinal nodular hamartomas; renal angiomyolipoma; Shagreen patch; SEGA; >=2 SENs; >=2 ungual fibromas. Minor features include sclerotic bone lesions; confetti skin lesions; dental enamel pits; intraoral fibromas; multiple renal cysts; nonrenal hamartomas; retinal achromic patch.

inv-18: Other multisystem inherited disorders — covered list and approach

Genetic testing to establish or confirm diagnosis of other multisystem inherited disorders listed below is medically necessary when clinical features consistent with the disorder are present:

Other multisystem disorders list: Genetic testing is medically necessary when clinical features consistent with listed multisystem inherited disorders are present (examples include Alagille, Alport, Branchiootorenal spectrum disorder, Coffin‑Siris, Cornelia de Lange, FGFR2 craniosynostosis syndromes, Holoprosencephaly, Holt‑Oram, Incontinentia pigmenti, Joubert/Meckel‑Gruber, Kabuki, MYH9‑related disorders, Proteus, Pseudoxanthoma elasticum, Rubinstein‑Taybi, Waardenburg, Schwannomatosis). The list is not comprehensive; other disorders evaluated per the General Approach to Genetic and Molecular Testing.

inv-19: CMA and panel testing — background and coverage stance

Policy background and coverage stance on chromosomal microarray (CMA) and multigene panels:

CMA first‑tier stance: Chromosomal microarray is considered a first‑tier diagnostic test for global developmental delay/intellectual disability, autism spectrum disorder, and multiple congenital anomalies per AAP and ACMG guidance; CMA is investigational for other indications such as isolated speech/language delay.

Panels stance: Autism/ID multigene panels lack sufficient evidence and are considered investigational; professional guidance recommends CMA, fragile X testing, and consideration of exome sequencing in selected cases.

inv-20: Imprinting disorders — Angelman and Prader-Willi testing criteria

Methylation and targeted analyses for imprinting disorders (Angelman and Prader‑Willi) are medically necessary when the clinical criteria are met; methylation testing is required to detect PWS across common mechanisms:

Imprinting disorder testing general: Molecular testing (SNRPN/UBE3A methylation analysis 81331, 15q11‑q13 FISH 88271/88273, UPD analysis 81402, imprinting center defect analysis) is indicated for individuals with clinical features suggestive of Angelman or Prader‑Willi per GeneReviews criteria; methylation analysis diagnoses PWS across deletion, UPD, and imprinting defects.

Testing sequence note: Recommended testing strategy: 1) methylation analysis; 2) if methylation normal proceed to deletion analysis; 3) if deletion normal consider UPD analysis; 4) if UPD normal proceed to imprinting defect analysis.

inv-21: Beckwith-Wiedemann Syndrome — Diagnostic testing

Beckwith‑Wiedemann Syndrome diagnostic testing is supported when clinical findings and molecular/genomic alterations align as follows:

BWS diagnostic rule: Diagnosis can be established in a proband with at least one Tier‑1 or Tier‑2 clinical finding AND either: (1) constitutional epigenetic/genomic alteration with abnormal methylation at 11p15.5; OR (2) a copy number variant of 11p15.5; OR (3) a heterozygous pathogenic variant in CDKN1C. Testing (H19/KCNQ1OT1 methylation 81401, del/dup 11p15 81479, UPD7 81402, CDKN1C sequencing/del‑dup) is medically necessary when criteria met.

inv-22: Silver-Russell Syndrome — Diagnostic testing

Silver‑Russell Syndrome diagnostic testing is supported when the Netchine‑Harbison clinical criteria are met:

SRS diagnostic rule: SRS is suspected in individuals meeting NH‑CSS criteria; molecular confirmation is warranted when 4 of 6 criteria are met (some cases with 3 of 6 may have positive molecular findings). Diagnostic molecular testing is indicated for hypomethylation at 11p15.5 or maternal UPD7 when clinical criteria met.

inv-23: CFTR sequencing, deletion/duplication, and intron poly-T/TG testing

CFTR sequencing, deletion/duplication, and intron poly‑T/TG analysis are medically necessary for diagnostic indications when one or more of the following are present:

CFTR diagnostic indications: Positive newborn screen, positive or intermediate sweat chloride values, clinical features suggestive of CF involving >=2 organ systems, or positive family history — extended CFTR analysis and/or CFTR functional analysis should be considered in such cases.

R117H reflex guidance: ACMG recommends reflex intron poly‑T/TG testing when R117H is detected and parental testing to determine cis/trans for interpretation in diagnostic contexts (e.g., CBAVD).

inv-24: CHD7 sequencing and deletion/duplication analysis

CHD7 sequencing and deletion/duplication analysis is medically necessary for individuals with CHARGE‑associated features:

CHD7 testing indications: Individuals with combinations of CHARGE findings (coloboma; choanal atresia; cranial nerve dysfunction including anosmia; facial palsy; sensorineural hearing loss; ear malformations; temporal bone abnormalities; cleft palate; tracheoesophageal anomalies; cardiovascular malformations; hypogonadotropic hypogonadism; developmental delay; growth deficiency; characteristic facial/hand features; brain MRI anomalies) should be considered for CHD7 testing.

inv-25: Fanconi anemia multigene panel and follow-up testing

Fanconi anemia genetic testing and follow‑up is supported when the diagnostic workflow and clinical/laboratory features indicate FA:

FA testing workflow: If chromosome breakage testing is positive or inconclusive, perform a Fanconi anemia multigene panel to identify causative variants; genetic testing is also indicated when clinical/laboratory features suggest FA, and for relatives to identify heterozygous carriers.

inv-26: Diagnostic FMR1 repeat and methylation analysis

Diagnostic FMR1 (Fragile X) testing (repeat and methylation analysis) is supported when recommended clinical indications are present:

FMR1 testing indications: Individuals with unexplained intellectual disability or developmental delay, males with unexplained autism, females with autism and compatible phenotype or family history, women with primary ovarian insufficiency before age 40, and individuals >=50 with progressive intention tremor/ataxia of unknown cause should be considered for FMR1 testing.

inv-27: HHT multigene panel

HHT multigene panel testing (including ACVRL1 and ENG at minimum) is supported for diagnostic and family testing indications:

HHT panel indications: Refer for diagnostic genetic testing to identify a causative mutation in families with clinically confirmed HHT; to establish diagnosis in relatives (including asymptomatic individuals or those desiring prenatal testing); or to assist diagnosis in individuals who do not meet full clinical criteria (Curaçao criteria).

HHT gene considerations: Panel should include ACVRL1 and ENG; consider SMAD4 when ENG and ACVRL1 are negative.

inv-28: HHT multigene panel

Covered when any guideline‑based HHT indications below are met:

HHT guideline indications: Diagnostic testing to identify a causative mutation in a family with clinically confirmed HHT; testing of relatives of an affected person (including asymptomatic individuals or those seeking prenatal testing); assisting diagnosis in individuals not meeting full clinical criteria.

inv-29: NF1 sequencing and/or deletion/duplication analysis

NF1 sequencing and/or deletion/duplication analysis is covered when guideline diagnostic criteria or specific clinical scenarios are met:

NF1 testing use cases: Genetic testing may be performed to confirm suspected NF1 in young children with only café‑au‑lait macules, to differentiate NF1 from Legius syndrome (SPRED1), for atypical presentations, or when a parent meets diagnostic criteria; single‑gene testing or rasopathy panels may be appropriate based on phenotype.

NF1 clinical feature examples: Member has at least one of: six or more café‑au‑lait macules (size thresholds defined), axillary/inguinal freckling, two or more neurofibromas or one plexiform neurofibroma, optic pathway glioma, two or more Lisch nodules, or a distinctive osseous lesion; or a biological parent meeting diagnostic criteria.

inv-30: NF2 sequencing and/or deletion/duplication analysis

NF2 sequencing and/or deletion/duplication analysis is covered when the clinical or tumor‑based criteria below are present:

NF2 testing indications: Pathogenic NF2 variant identified on tumor tissue testing; OR adult with bilateral vestibular schwannomas; OR unilateral vestibular schwannoma plus >=2 additional tumor types (meningioma, schwannoma, glioma, neurofibroma, cataract); OR multiple meningiomas with associated features; OR a child with >=2 of the pediatric feature list (schwannoma, skin plaques, meningioma, cortical wedge cataract, retinal hamartoma, mononeuropathy).

inv-31: Noonan spectrum disorders multigene panel

Noonan spectrum/RASopathy multigene panel testing is covered when the clinical phenotype or family history suggests a RASopathy:

Noonan/RASopathy panel indications: Characteristic facies, congenital heart defects (e.g., pulmonary valve stenosis, hypertrophic cardiomyopathy), short stature, developmental delay, lymphatic dysplasia, broad/webbed neck, chest deformity, widely spaced nipples, cryptorchidism, lentigines, or café‑au‑lait macules. Consider single‑gene PTPN11 testing first in some presentations.

inv-32: PIK3CA sequencing analysis

PIK3CA sequencing analysis is covered when clinical presentation is consistent with PIK3CA‑Related Overgrowth Spectrum (PROS):

PIK3CA testing indications: Consider testing in individuals with congenital or early‑childhood onset segmental/focal overgrowth, vascular or lymphatic malformations, cutaneous findings (epidermal nevi, hyperpigmented macules), digital anomalies, kidney malformations, benign tumors (excluding Wilms tumor), or focal brain overgrowth findings (hemimegalencephaly, focal cortical dysplasia, dysplastic megalencephaly).

PIK3CA testing practical note: Because many pathogenic variants are mosaic, testing of multiple tissue types may be required; a negative result does not exclude the diagnosis.

inv-33: TSC1/TSC2 sequencing and deletion/duplication analysis

TSC1/TSC2 sequencing and deletion/duplication analysis is covered when genetic or clinical diagnostic criteria for Tuberous Sclerosis Complex are present:

TSC testing indications: Identification of a pathogenic variant in TSC1 or TSC2 is sufficient for diagnosis and is recommended for genetic counseling or when TSC is suspected; genetic testing is indicated when the proband has >=1 major feature or >=2 minor features per consensus diagnostic criteria.

TSC major/minor features summary: Major and minor features are listed in policy (major examples: angiofibromas>3, cardiac rhabdomyoma, cortical tubers, hypomelanotic macules>=3; minor examples: sclerotic bone lesions, confetti skin lesions, dental enamel pits, intraoral fibromas, multiple renal cysts).

Covered Indications and Diagnostic Situations

CPT/HCPCS Codes and Coding Guidance

Covered CPT Codes — Chromosomal MicroarrayCPTCovered

81228	Chromosomal microarray analysis
81229	Chromosomal microarray analysis (additional descriptor in doc)
S3870	Chromosomal microarray analysis (HCPCS example listed)

Covered CPT Codes — Methylation/Angelman-Prader-WilliCPTCovered

81331

SNRPN/UBE3A methylation analysis

Covered CPT Codes — Fragile X (FMR1)CPTCovered

81243	FMR1 DNA diagnostic testing (Fragile X) repeat expansion
81244	FMR1 methylation analysis (Fragile X) / related

Covered CPT Codes — Multigene panels and other molecular tests (examples)CPTCovered

81405	Targeted multigene panel (example listed for HHT, TSC)
81406	Targeted multigene panel (example listed)
81162	Large gene deletion/duplication (example listed for Fanconi anemia)
81307	Sequence analysis/other codes referenced for panels
81479	Unlisted molecular pathology procedure (used as example)

Covered CPT Codes — FISH and UPDCPTCovered

88271	FISH analysis (e.g., 15q11-q13)
88273	FISH analysis (additional)
81402	Uniparental disomy analysis

Chromosomal Microarray / CMACPTCovered

81228	Chromosomal microarray analysis (CMA)
81229	Chromosomal microarray analysis (CMA) add-on/related
S3870	Genomic micro-array (HCPCS example cited)

Angelman/Prader-Willi testingCPTCovered

81331	Methylation analysis (SNRPN/UBE3A; imprinting)
88271	FISH analysis (15q11-q13 deletion)
88273	FISH analysis (15q11-q13 deletion) — higher complexity
81402	Uniparental disomy analysis

Beckwith-Wiedemann/Russell-Silver testingCPTCovered

81401	Methylation analysis (H19, KCNQ1OT1)
81479	Unlisted molecular pathology procedure / deletion/duplication (used here for 11p15 del/dup, CDKN1C)

Cystic Fibrosis testingCPTCovered

81222	CFTR sequencing
81223	CFTR deletion/duplication analysis
81224	CFTR intron 9 polyT and TG analysis

CHARGE syndrome testingCPTCovered

81407	CHD7 sequencing
81479	Deletion/duplication analysis (CHD7)

Fanconi anemia multigene panelCPTCovered

81162	Targeted sequence analysis (used in Fanconi anemia multigene panel contexts)
81307	Deletion/duplication analysis (Fanconi anemia genes)
81479	Unlisted molecular pathology procedure (multigene panel)

Fragile X testingCPTCovered

81243	FMR1 repeat analysis
81244	FMR1 methylation analysis

Hereditary Hemorrhagic Telangiectasia panelCPTCovered

81405	HHT multigene panel (single gene sequencing)
81406	HHT multigene panel (multiple genes)
81479	Unlisted molecular pathology procedure (panel)

Neurofibromatosis 1 testingCPTCovered

81408

NF1 sequencing and/or deletion/duplication analysis

NF2-related schwannomatosis testingCPTCovered

81405	NF2 sequencing (also used above for panels)
81406	NF2 multigene/panel sequencing

Noonan spectrum/RASopathy panelCPTCovered

81442

Noonan spectrum disorders / RASopathy multigene panel

PIK3CA sequencingCPTCovered

81479

PIK3CA sequencing analysis (listed as 81479 in this document)

PIK3CA sequencingCPTCovered

81479

PIK3CA sequencing analysis (as listed)

TSC1/TSC2 sequencing and deletion/duplicationCPTCovered

81405	TSC1 sequencing and/or deletion/duplication analysis
81406	TSC2 sequencing and/or deletion/duplication analysis
81407	TSC1/TSC2 panel or combined testing

Referenced CPT CodesCPT

81408

Single-gene or targeted sequencing panel code referenced as considered medically necessary in NF1 context (per policy edits)

Referenced CPT/HCPCS codes added/removed/updated in this excerptmixed

81408	CPT referenced and added as medically necessary in at least one section
81415	Genomic Unity Exome Analysis - Proband (example test added/replaced in reference table)
81416	Genomic Unity Exome Analysis - Comparator (Duo or Trio) (example test added/replaced in reference table)
81216	Code removed from sections (listed as removed)
81405	Code removed from sections (listed as removed)
81479	Code removed from sections (listed as removed)
S3870	HCPCS code added to policy (mentioned as added)

Age for CMA recommendation

Recommended age groupChildren with developmental delay or clinical diagnosis of intellectual disability (policy references pediatric indications for CMA)

ExclusionIsolated speech/language delay is excluded from CMA indication

Reference guidanceWashington State Health Care Authority Billing Guidelines and 'Genomic Micro-array' Health Technology Assessment

Macrosomia centile cutoff

Macrosomia cutoff (examples)>90th or >97th centile (used in BWS macrosomia definition)

ContextApplied as a Tier 1 clinical feature for Beckwith‑Wiedemann Syndrome

Source statement'Macrosomia, defined as pre- and/or postnatal overgrowth, often using a cutoff of >90th or >97th centile'

Sweat chloride diagnostic cutoff (Cystic Fibrosis)

Diagnostic sweat chloride cutoff>= 60 mmol/L = positive for cystic fibrosis; 30–59 mmol/L = intermediate/inconclusive

Alternate triggers for CFTR testingPositive newborn screen with elevated IRT or symptoms from ≥2 organ systems may prompt CFTR sequencing/del-dup

Policy noteCFTR sequencing/deletion-duplication analysis considered investigational for indications not meeting listed criteria

Café au lait macules count and size

Café au lait macules (CALMs)Six or more CALMs >5 mm in greatest diameter in prepubertal individuals; >15 mm in postpubertal individuals

Associated featuresAxillary/inguinal freckling, neurofibromas, optic glioma, Lisch nodules and osseous lesions support NF1 evaluation

UseNumeric CALM threshold used as one diagnostic criterion to consider NF1 genetic testing

NF1 clinical feature counts

NF1 numeric feature thresholdAt least six café-au-lait macules (size thresholds noted) or other listed NIH diagnostic features (e.g., freckling, two or more neurofibromas, optic glioma, two or more Lisch nodules) constitute criteria to consider NF1 testing

Examples of qualifying clinical featuresFreckling in axillary/inguinal regions; two or more neurofibromas or one plexiform neurofibroma; optic pathway glioma; distinctive osseous lesion; parent meeting diagnostic criteria

Policy change notePolicy added numeric and enumerated NF1 clinical feature criteria and references CPT 81408 as medically necessary in this context

Provider Actions, Prior Authorization, and Documentation Requirements

Prior Authorization

Verify coding and authorization expectations

Coding examples in the policy are illustrative only; verify the applicable CPT/HCPCS codes and whether prior authorization is required through the Concert Genetics Platform or the member's Health Plan prior authorization processes before ordering or submitting claims.

Prior Authorization

CMA prior authorization expectation

Chromosomal microarray analysis (CMA: 81228, 81229, S3870) is considered medically necessary in children for GDD/ID, ASD, or congenital anomalies when the policy's listed clinical criteria are met; ensure documentation meets the stated criteria before requesting authorization.

Prior Authorization

Medical necessity required for listed CPT codes

Testing submitted under the CPT codes listed in the policy (e.g., PIK3CA 81479; TSC1/TSC2 81405–81407) must meet the policy's medical necessity criteria (specific clinical features or imaging) to be covered; lack of qualifying findings may result in denial.

Prior Authorization

Prior authorization may be required for diagnostic genetic testing

Prior authorization may be required for diagnostic genetic testing; confirm and obtain any required authorization for the specific genetic test ordered (for example, extended CFTR analysis and reflex intron testing per ACMG guidance).

Prior Authorization

Prior authorization for specified genetic tests

Certain single-gene or panel tests (policy references contexts including CPT 81408) are designated medically necessary only when the member meets listed clinical criteria; follow payer prior authorization processes for these tests.

Prior Authorization

Use updated exome example codes for prior auth

When requesting prior authorization for exome testing, use the updated example codes noted in the policy reference table (example: replace example Variantyx entries with 81415 for Proband and 81416 for Comparator/Duo/Trio in authorization requests).

Prior Authorization

Prior authorization and coverage subject to plan terms

Coverage decisions and payment remain subject to the member's coverage documents and Health Plan administrative procedures; confirm plan-level prior authorization and benefit terms before ordering testing.

Step Therapy

Angelman/Prader‑Willi: recommended sequential testing

For Angelman/Prader‑Willi suspected cases, follow the recommended sequential testing approach: start with SNRPN/UBE3A methylation analysis, then deletion (15q11–q13) analysis if methylation is normal, then UPD analysis, and finally imprinting‑center defect analysis if prior steps are normal.

1) SNRPN/UBE3A methylation analysis (81331)
2) If methylation normal → deletion analysis of 15q11–q13 (FISH 88271/88273)
3) If deletion normal → chromosome 15 UPD analysis (81402)
4) If UPD normal → imprinting defect analysis (81331)

Step Therapy

CMA is first‑tier for GDD/ID/ASD

Chromosomal microarray (CMA) is recommended as a first‑tier diagnostic test for global developmental delay/intellectual disability, autism spectrum disorder, or multiple congenital anomalies in children; avoid ordering CMA for isolated speech/language delay, which is considered investigational.

Step Therapy

Noonan syndrome: sequential testing (PTPN11 first‑tier option)

For suspected Noonan syndrome, consider sequential testing: single-gene PTPN11 testing may be an appropriate first‑tier test given approximately 50% detection rate prior to broader multigene panel testing.

If PTPN11 negative and phenotype persists → proceed to Noonan/RASopathy multigene panel (81442)

Note

Documentation Required

Documentation and coding guidance reminder

Follow current CPT coding and professional coding guidance when ordering and billing genetic tests; the policy's code examples are illustrative and do not guarantee coverage—verify code selection and claim submission details prior to billing.

Documentation Required

PIK3CA: document tissue types and mosaicism considerations

For PIK3CA testing, document the tissue type(s) tested (e.g., blood, skin, saliva) because most reported pathogenic PIK3CA variants are mosaic and more than one tissue type may need testing; note that a negative result does not exclude diagnosis due to low‑level mosaicism.

Provide brain imaging findings that support testing (e.g., hemimegalencephaly, focal cortical dysplasia) per the policy's criteria.
If multiple tissues tested, document each specimen source and rationale.

Documentation Required

GDD documentation requirements

For Global Developmental Delay (GDD) indications, include norm‑referenced, age‑appropriate standardized developmental measures administered by experienced developmental specialists, or clear documentation of profound delays based on milestones, when submitting testing requests.

Documentation Required

PIK3CA: include imaging findings and tissues tested

When requesting PIK3CA testing, include relevant imaging findings (brain imaging) and explicitly list the tissue types submitted for testing to support medical necessity and interpretation in the setting of mosaicism.

Documentation Required

Document condition‑specific clinical findings and family history

Document the condition‑specific clinical findings and relevant family history that correspond to the disorder-specific criteria (for example: tier 1/tier 2 features for Beckwith‑Wiedemann, NH‑CSS elements for Silver‑Russell, CF clinical signs or newborn screen/sweat chloride results for CFTR testing, Curaçao criteria or family history for HHT).

For CFTR testing, include newborn screen results or sweat chloride values when applicable.
For HHT, note family members with confirmed HHT or the number of Curaçao criteria met.

Documentation Required

Angelman/Prader‑Willi testing strategy: document sequential steps

Use the policy's recommended testing strategy for Angelman/Prader‑Willi (methylation → deletion → UPD → imprinting defect) and document each step and results in the medical record when proceeding through the sequence.

Prior Authorization

PIK3CA testing: criteria and recommended diagnostic documentation

When ordering PIK3CA sequencing, follow the policy's sequential/criteria‑based approach: ensure brain imaging findings and at least one early‑onset overgrowth or related clinical feature are documented to meet medical necessity prior to testing.

Document brain imaging findings (hemimegalencephaly, focal cortical dysplasia, or dysplastic megalencephaly) if present.
List the early‑onset overgrowth or vascular/lymphatic/cutaneous/digital/renal/benign tumor feature(s) present.

Documentation Required

Sequential testing: document rationale and follow‑up plan

When pursuing sequential testing (e.g., PTPN11 before a RASopathy panel, or stepwise Angelman/Prader‑Willi testing), document the rationale for performing the initial test and the plan for subsequent testing if initial results are non‑diagnostic.

Denial Risk

Coding guidance and denial risk: verify indications and documentation

Confirm code selection, clinical indication, and required documentation prior to submitting claims—failure to meet the revised condition‑specific criteria or to supply the documented clinical findings required in each disorder section may trigger denial.

Inclusion/exclusion of codes in the policy does not guarantee coverage.
Tests not meeting listed criteria or lacking documentation are at risk for denial.

Note

Investigational or Not Covered Testing

The inclusion of CPT codes, example tests, and laboratory names in this policy is for informational purposes only and does not guarantee coverage. Providers must verify applicable coding and coverage requirements with the payer and reference the most current professional coding guidance and the Concert Genetics Platform for the authoritative list of registered tests and labs. Claims remain subject to the member's coverage documents, plan terms, and Health Plan administrative procedures.

Multigene panels for autism spectrum disorder (ASD) or intellectual disability (ID) are considered investigational when used outside the condition‑specific criteria. Example CPTs and test identifiers listed in the policy for ASD/ID panels include 0156U, 81470, 81471, 81479, 81185, 81236, 81302, and 81321; the policy states these panel uses are investigational and therefore not supported for routine coverage for ASD/ID outside the specified clinical indications and guidance.

Testing for PIK3CA (example CPT 81479) and TSC1/TSC2 sequencing and deletion/duplication analysis (examples: 81405, 81406, 81407) is covered only when the policy's specific clinical criteria are met. These tests are considered investigational when ordered for indications not enumerated in the policy. Additionally, chromosomal microarray analysis (CMA) is considered investigational for isolated speech/language delay due to low diagnostic yield and is not supported for that isolated indication.

Tests and procedures ordered outside the policy's stated clinical criteria or without the required clinical documentation are not supported by the policy. The document emphasizes that examples of tests and CPT codes are illustrative; ordering tests that do not meet the condition‑specific criteria, family history requirements, or documented diagnostic triggers risks denial as not medically necessary or investigational.

The policy underwent multiple editorial updates, including targeted removals and code corrections. These edits (for example, replacement of some example exome tests with CPTs 81415 and 81416 and other line‑item changes) reflect operational housekeeping and do not in themselves constitute an explicit list of tests that are categorically not covered. Where tests or codes were removed or relabeled, the policy retains the guiding principle that inclusion of codes/examples does not guarantee coverage.

Two conditions were removed from this policy's 'Other Covered Multisystem Inherited Disorders' list and will be addressed under different policies: Cerebral cavernous malformations and SHOX deficiency disorders. The document notes these condition moves in its revisions but does not change the general approach that testing coverage is determined by the receiving policy's clinical criteria.

Definitions and Terminology

Genetic testing for multisystem inherited disorders is intended to establish or confirm a diagnosis in patients whose clinical evaluation and standard testing have been non‑diagnostic or inconclusive. A confirmed genetic diagnosis can inform medical and behavioral management, enable appropriate surveillance, guide family planning, and may obviate additional diagnostic procedures. This policy focuses on commonly encountered multisystem conditions where molecular, cytogenetic, or epigenetic testing (for example, CMA, targeted sequencing, methylation, FISH, or multigene panels) can directly impact care.

Chromosomal microarray analysis (CMA) definition

DefinitionChromosomal microarray analysis (CMA): genomic microarray testing (examples: CPT 81228, 81229, HCPCS S3870) used to detect copy number variants as a diagnostic test in children with developmental delay, intellectual disability, autism spectrum disorder, or congenital anomalies

Primary useFirst‑tier diagnostic test for GDD/ID/ASD and multiple congenital anomalies per AAP/ACMG guidance

Coverage contextMedically necessary when specified clinical criteria are met; investigational for isolated speech/language delay

Chromosomal Microarray Analysis (CMA) — code examples and brief definition

Example CPT codes81228, 81229, S3870 (examples cited for CMA)

Brief definitionCMA: array-based testing to detect copy number variants for diagnostic evaluation of developmental delay, intellectual disability, ASD, or congenital anomalies

Coverage noteConsidered medically necessary in children when specified clinical criteria are met (see CMA section)

Methylation analysis / UPD testing definition

DefinitionMethylation analysis/UPD testing: molecular assays (examples: 81331 methylation; 81402 UPD) used to detect imprinting abnormalities, uniparental disomy, or methylation defects for diagnosing imprinting disorders such as Angelman, Prader‑Willi, Beckwith‑Wiedemann, and Silver‑Russell syndromes

Typical use sequenceFor Angelman/Prader‑Willi: start with methylation analysis; if normal proceed to deletion analysis, then UPD analysis, then imprinting center defect analysis

Example targetsH19 and KCNQ1OT1 methylation analysis and 11p15 deletion/duplication analysis for BWS; chromosome 7 UPD testing for Russell‑Silver

Close relatives definition

Definition of close relativesFirst‑degree: parents, siblings, children; Second‑degree: grandparents, aunts/uncles, nieces/nephews, grandchildren, half‑siblings; Third‑degree: great grandparents, great aunts/uncles, great grandchildren, first cousins

UsageReferenced for interpreting family history criteria across condition-specific recommendations (e.g., HHT, BWS, fragile X)

Policy noteClose relative degrees are used to define at‑risk family members for cascade or diagnostic testing

Global Developmental Delay (GDD) definition

DefinitionGlobal Developmental Delay (GDD): significant delay in two or more developmental domains requiring standardized, age‑appropriate, norm‑referenced assessment; used for children younger than 5

Documentation requirementAssessment should be administered by experienced developmental specialists or documentation of profound delays based on milestones

Relation to testingGDD qualifies as an indication for CMA when criteria met (CMA is first‑tier)

Intellectual Disability (ID) definition

DefinitionIntellectual Disability (ID): lifelong disability typically diagnosed at or after age 5 when IQ testing is valid (IQ <70) with onset during childhood and impairment in adaptive behavior

Distinction from GDDGDD applies to children <5; ID is diagnosed at/after age 5 when formal IQ assessment is valid

Relation to testingID is an indication for CMA when clinical criteria are met

Tier 1 and Tier 2 clinical findings (BWS)

Tier 1 findings (BWS)Highly suggestive features (examples): macroglossia, omphalocele/abdominal wall defect, embryonal tumor (e.g., Wilms), hemihyperplasia, macrosomia (>90th or >97th centile), hyperinsulinemic hypoglycemia

Tier 2 findings (BWS)Less specific features: visceromegaly, ear creases/pits, characteristic facies, kidney anomalies, large umbilical hernia, transient hypoglycemia

Diagnostic ruleDiagnosis of BWS can be established with ≥1 tier 1 or tier 2 clinical finding plus a specified molecular/genomic alteration (11p15 methylation change, 11p15 CNV, or pathogenic CDKN1C variant)

Netchine-Harbison clinical scoring system (NH-CSS) for Silver-Russell syndrome

NH-CSS componentsSix clinical items: small for gestational age; postnatal growth failure; relative macrocephaly at birth; frontal bossing; body asymmetry; feeding difficulties or low BMI/feeding support

Diagnostic thresholdMeeting 4 of 6 NH‑CSS features warrants molecular confirmation testing for Silver‑Russell syndrome; some with 3 of 6 have positive molecular findings

Molecular correlatesMolecular confirmation: hypomethylation at 11p15.5 or maternal UPD7

TSC diagnostic criteria

TSC diagnostic rule (summary)Definite TSC: 2 major features OR 1 major + 2 minor; identification of a pathogenic TSC1 or TSC2 variant is sufficient for diagnosis and supports early surveillance

Family historyObtain a three‑generation family history to determine at‑risk relatives; genetic testing recommended for counseling or when clinical diagnosis unclear

Clinical criteria usePresence of ≥1 major or ≥2 minor features should prompt consideration of genetic testing

Diagnostic testing — distinction diagnostic vs carrier testing (CFTR example)

Diagnostic vs carrier testing distinctionSection clarifies 'Diagnostic CFTR Sequencing and/or Deletion/Duplication Analysis' to distinguish diagnostic testing from carrier screening; diagnostic testing is indicated for clinical presentations (e.g., positive newborn screen, sweat chloride, congenital absence of vas deferens)

Example (CFTR)Reflex intron poly‑T/TG analysis (81224) recommended when R117H is detected per ACMG; diagnostic testing may be covered even without preceding sweat testing in some scenarios per consensus

Policy implicationOrdering documentation should align with diagnostic vs carrier intent to support coverage

Reference sources (GeneReviews, ACMG, guideline citations)

Reference sources listedGeneReviews and ACMG technical standards and guidelines are cited repeatedly as primary references for condition criteria and testing standards

Examples of cited sourcesGeneReviews entries (e.g., BWS, SRS, CHD7, FMR1, PIK3CA, TSC), ACMG practice resources and technical standards (e.g., CFTR variant testing)

Use in policyReferences support clinical criteria, diagnostic workflows, and technical testing recommendations across sections

Eligibility and Applicability

Eligibility requirements for coverage of genetic testing are defined by the condition‑specific criteria in this policy and by the member's plan documents. Providers should document clinical findings, standardized testing results (when applicable), and relevant family history to demonstrate that the ordered test meets the policy's stated indications. For Medicaid members, state Medicaid provisions take precedence if they conflict with this clinical policy.

Clinical documentation should include a focused three‑generation family history when indicated (for example, TSC and HHT), and relevant diagnostic testing results or imaging. Providers are expected to show how the member meets the specific clinical thresholds or guideline‑based criteria cited in each disorder section (e.g., NH‑CSS features for Silver‑Russell, café‑au‑lait counts for NF1, or sweat chloride results for CFTR testing). Failure to document required findings may result in denial.

For children with global developmental delay, intellectual disability, autism spectrum disorder, or multiple congenital anomalies, chromosomal microarray analysis (CMA) is considered a first‑tier diagnostic test when the clinical criteria are met. CMA is investigational for other indications, including isolated speech/language delay, and should not be ordered as a first‑line test for those isolated presentations.

For suspected Angelman or Prader‑Willi syndromes the recommended testing sequence begins with SNRPN/UBE3A methylation analysis (example CPT 81331); if methylation testing is normal, the policy recommends proceeding to deletion analysis (e.g., FISH 88271/88273), then uniparental disomy analysis (example CPT 81402), and finally imprinting center defect analysis if prior testing is unrevealing. These steps must align with the syndrome‑specific clinical criteria described in the policy.

For PIK3CA‑related segmental overgrowth disorders, testing is medically necessary when the member has supportive brain imaging findings (for example, hemimegalencephaly or focal cortical dysplasia) and at least one early‑onset overgrowth or related clinical feature. Because pathogenic variants are often mosaic, documentation should indicate tissue types tested and, when applicable, results from multiple tissues; a negative result does not exclude the diagnosis.

For suspected Tuberous Sclerosis Complex (TSC), genetic testing of TSC1 and TSC2 (sequencing and deletion/duplication analysis; examples 81405, 81406, 81407) is medically necessary when the proband has at least one major clinical feature or at least two minor features as defined in the policy. Identification of a pathogenic variant is sufficient for diagnosis and may prompt early surveillance and cascade testing of relatives.

Fanconi anemia multigene panel testing (examples: 81162, 81307, 81479) is medically necessary when a prior chromosome breakage test is positive or inconclusive and the proband has at least one of the listed clinical or laboratory findings (for example, short stature, abnormal skin pigmentation, skeletal malformations, cytopenias, or early‑onset malignancy). Panels are investigational for other indications.

FMR1 repeat and methylation analysis (examples 81243, 81244) is considered medically necessary to evaluate unexplained intellectual disability or developmental delay, males with unexplained autism, females with primary ovarian insufficiency, or older adults with progressive intention tremor and cerebellar ataxia, when the clinical criteria or family history are consistent with Fragile X syndrome or associated disorders.

Diagnostic CFTR testing (sequencing, deletion/duplication, and intron poly‑T/TG analysis; examples 81222, 81223, 81224) is supported when a patient has a positive newborn screen, clinical features suggestive of cystic fibrosis, a positive family history, or intermediate sweat chloride values on two occasions. ACMG/CF Foundation guidance requires reflex intron poly‑T/TG testing when certain variants (e.g., R117H) are identified.

Hereditary Hemorrhagic Telangiectasia (HHT) multigene panel testing is medically necessary when guideline‑based indications are met, such as the presence of Curaçao criteria features (recurrent epistaxis, mucocutaneous telangiectases, visceral AVMs) or a first‑degree relative with confirmed HHT. Panels should include at minimum ACVRL1 and ENG, and consider SMAD4 if ENG and ACVRL1 are negative.

The policy's recent revisions included condition‑specific wording changes, numeric thresholds added to some criteria (for example, café‑au‑lait counts for NF1), removal or correction of certain example codes, and consolidation of known familial‑variant testing into a general approach policy. Providers should use the updated criteria and reference table when documenting medical necessity for genetic testing requests.

Background and Rationale

Genetic testing is intended to improve diagnostic precision for multisystem disorders and inform management decisions. When clinical features, standardized assessments, and family history align with the documented policy criteria, ordered molecular or cytogenetic tests may be considered medically necessary and eligible for coverage subject to plan terms.

Revision History and Policy Changes

2026-06-01policy_effectiveLatest

Policy effective date updated to 2026-06-01 reflecting the consolidated Concert Genetics guidance for multisystem inherited disorders, intellectual disability, and developmental delay.

2026-04-26content_revision

Extensive condition-specific revisions implemented (NF1, NF2, Noonan/RASopathies, PIK3CA, TSC, CFTR, Angelman/Prader-Willi, Beckwith-Wiedemann/Russell-Silver), including reworded criteria, added numeric clinical feature thresholds for NF1, and removal/replacement of certain example CPTs.

2026-04-26coding_update

Reference/test list updates: removed selected example tests (e.g., certain exome examples), removed codes (examples cited), and added explicit mention that CPT 81408 is considered medically necessary in an NF1 context; exome example tests corrected to 81415/81416 in the reference table.

2026-04-26guideline_incorporation

Specialty guideline text and recommendations (e.g., HHT, AAP NF1, International TSC Consensus, CF consensus) were incorporated to support revised testing indications and background rationale.

Operational edits in this revision include multiple code and reference‑table updates: example exome tests were corrected to CPT 81415 and 81416, HCPCS S3870 was added, and some example CPTs were removed or replaced. These changes are administrative and intended to align example test names and codes with the current marketplace and internal reference table.

For Medicaid members/enrollees, state Medicaid coverage provisions supersede this clinical policy when conflicts exist. Providers must consult state Medicaid manuals and plan documents to determine final coverage rules and any state‑specific exceptions.

The policy clarifies and reorganizes the CMA and methylation/UPD sections: CMA is affirmed as first‑tier testing for GDD/ID/ASD per AAP and ACMG guidance, while methylation and targeted analyses (SNRPN/UBE3A methylation, 15q11‑q13 FISH, UPD analysis, imprinting center testing) remain the recommended diagnostic sequence for imprinting disorders such as Angelman and Prader‑Willi. The Angelman/Prader‑Willi testing sequence and age‑specific criteria are explicitly described in the policy.

The excerpt documents several coding updates across the policy reference table and condition sections: some example CPTs and proprietary example tests were removed or replaced (e.g., Variantyx example codes were corrected to 81415 and 81416), HCPCS S3870 was added for CMA examples, and explicit mention of CPT 81408 was added in at least one section. These referenced edits are intended to align policy examples with current coding practice and do not themselves alter clinical criteria unless explicitly stated in the condition sections.