Next-generation sequencing of targeted gene panels in the diagnosis of hereditary cardiomyopathies - INAHTA Brief

Aim

The objective of this evaluation was to determine the benefit of using targeted next-generation sequencing (NGS) and gene panel analysis for identifying the molecular alterations responsible for hereditary cardiomyopathies in routine clinical practice. The aims were to define:

• the composition of the gene panels of interest to be sequenced and analyzed by NGS (from a blood sample);
• the relevance of using gene panel analysis by NGS compared with other available techniques (medical value assessed by the diagnostic yield of the method and the clinical utility of the test);
• the role of gene panel analyses in the diagnostic and therapeutic management strategy of hereditary cardiomyopathies.

Conclusions and results

The HAS considers that targeted next-generation sequencing (NGS) of a gene panel is justified in the following situations:

• As a first-line test, for the genetic diagnosis of patients with a confirmed cardiac disease and a cardiomyopathy phenotype suspected to be hereditary, after an initial clinical evaluation has failed to establish a precise diagnosis;
• As a second-line test, when a genetic cause is still suspected in patients presenting with specific cardiomyopathy phenotypes (such as TTR amyloidosis, Fabry disease, or laminopathies), after an initial clinical evaluation and a negative result from a monogenic test (no causal variant identified).

In these indications, the gene panels used to identify relevant molecular alterations have the following compositions:

• Panel of 18 genes for the diagnosis of hypertrophic cardiomyopathy: ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNI3, TNNT2, TPM1, GLA, LAMP2, PRKAG2, TTR, FHL1, FLNC, ACTN2, TNNC1, ALPK3, FHOD3 (in case of a negative result, a broader panel covering the various forms of cardiomyopathies may be recommended);
• Panel of 48 genes for the diagnosis of the different forms of cardiomyopathies (dilated, arrhythmogenic, restrictive, and left ventricular non-compaction cardiomyopathies) : ACTC1, ACTN2, ALPK3, BAG3, CSRP3, DES, DMD, DSC2, DSG2, DSP, EMD, FHL1, FHOD3, FLNC, GAA, GLA, JPH2, JUP, KRAS, LAMP2, LMNA, MYBPC3, MYH7, MYL2, MYL3, MYPN, NEXN, NKX2-5, PKP2, PLN, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SOS1, TAFAZZIN, TBX5, TBX20, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, VCL.

The HAS considers that the analysis of targeted gene panels using NGS has significant clinical utility as it allows:

• the simultaneous identification of alterations in multiple genes;
• the detection of rare or multiple variants not identifiable by more targeted techniques;
• the identification of complex cases with associated syndromes;
• the guidance and personalization of patient management (for instance, implantation of medical devices when certain genetic variants are present, or specific drug prescriptions in syndromic cases);
• the screening of relatives to assess genetic risk, implement appropriate cardiological follow-up, and apply preventive measures.

Regarding the conditions of implementation, HAS emphasizes that a legal framework exists for gene panel analyses (bioethics laws, laboratory activity authorizations, and health professional accreditations). It also recommends, given the specific clinical context of these rare diseases:

• that analyses be performed in specialized laboratories linked to rare disease reference centers, particularly those within the Cardiogen network;
• that prescribers work within a multidisciplinary framework in collaboration with these expert centers;
• that family analyses be centralized to improve result interpretation;
• that patients receive clear and comprehensive information;
• that results be communicated within a reasonable timeframe to allow appropriate management of the suspected pathology.

Recommendations

The HAS recommends coverage of targeted high-throughput gene panel sequencing for patients suspected of hereditary cardiomyopathies in the situations and indications mentioned above.

Methods

The assessment method used in this report is based on: 

• a critical analysis of the synthesized literature (thirteen clinical practice guidelines, two health technology assessment reports, and four systematic reviews) identified through a systematic search and selected according to explicit criteria. ;
• consultation of a group of experts of several healthcare professionals,
• consultation of professional bodies, patients’ associations and public health institutions concerned by the subject, questioned as stakeholders in order to collect their collective points of view on a draft version of the report containing the elements collected previously and the conclusions that could be drawn from them.

The conclusions were reviewed by the Diagnostic, Prognostic and Predictive Health Technologies Evaluation Committee (CEDiag), the HAS specialized appraisal committee, and then approved by the HAS College.

Further research/reviews required

The HAS points out that the composition of gene panels may be subject to change if new genetic alterations are identified in certain genes. HAS will conduct new evaluations in response to advances in scientific knowledge (identification of new relevant evidence and/or publication of new French National Authority for Health Transparency Committee advice).