Genetic testing for hypertrophic cardiomyopathy (HCM) (R131)

Background information

Hypertrophic cardiomyopathy (HCM) is associated with dyspnoea, chest pain, palpitations and an increased risk of sudden death. Individuals with more than one pathogenic variant typically present at a younger age and with a more severe phenotype compared to patients with one pathogenic variant.

Currently there are 20 genes (ACTC1, ACTN2, CSRP3, FHL1, FHOD3, FLNC, GLA, JPH2, LAMP2, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, TNNC1, TNNI3, TNNT2, TPM1, and TTR) and two variants; p.Arg518 in CACNA1C and the mitochondrial variant MT-TI m.4300A>G on the panel.

MYBPC3 and MYH7 account for around a third of HCM cases. Variants are more rarely found in the other well-characterised HCM genes on this panel.

This panel may identify other disorders where HCM is part of the clinical presentation. These account for fewer than two percent of cases for each gene.

These other disorders include the following.

• Wolff-Parkinson-White syndrome due to autosomal dominant with usually de novo pathogenic variants in PRKAG2 gene
• Anderson-Fabry Disease (AFD) maybe identified using this panel is caused by pathogenic variants in the GLA gene. The vast majority are point mutations, although large-scale deletions or duplications have been detected
  
• Danon disease is caused by loss-of-function variants in the LAMP2 gene, which encodes lysosome-associated membrane protein 2
• MYH7-related skeletal myopathies include Laing early-onset distal myopathy, myosin storage myopathy (hyaline body myopathy), and scapuloperoneal myopathy, usually caused by missense changes in the myosin tail domain
  

Testing strategy

Clinically affected probands:

R131 - Singleton analysis of a medium panel of genes. Data from the entire coding region of the main transcripts of ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, and TPM1 is always included.

Targeted analysis for known / previously reported familial variants:

• Family testing in clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)
• Diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
• Segregation studies in affected family members to aid variant interpretation (R375)
• Prenatal diagnosis for families with a pathogenic or likely pathogenic variant identified (R240 and R321 Maternal cell contamination)

Target reporting times

• 84 calendar days for diagnostic screening of affected individuals
• 42 calendar days for diagnostic confirmation in individuals at risk of inheriting a previously reported familial pathogenic variant and clinically suspected of having the familial condition (R240)
• 14 calendar days for presymptomatic testing of clinically unaffected family members at risk of inheriting a previously reported familial pathogenic variant (R242)

Turnaround times for genetic / genomic testing

Speciment requirements and referring samples

All non NHSE referrals should be accompanied by a completed referral form.

Requesting specialties:

• Cardiology
• Clinical Genetics
• Paediatrics
• Electrophysiology
• Pathology
• Coroners

Specimen requirements and referring samples

Price list for non NHSE referrals (pdf)