May 2019 | Bealtaine 2019

Managing Uncertainty in Inherited Cardiac Pathologies

Mon, 20 May 19 16:35

An International Multi-Disciplinary Survey

Advances in broad-based genetic analysis has resulted in substantially increased quantities of diagnostic data in a very time-efficient and cost-efficient manner.  However, in oligogenic conditions, such analysis may provide essential information to guide therapy but also generates information of unknown significance.  As heritable cardiac pathologies can be phenotypically and genotypically diverse, whole exome or whole genome sequencing can result in variants of certain, likely or uncertain pathogenicity.  This range of possible outcomes raises concerns about the management of variants of uncertain pathogenicity. 

As the average human genome contains between 4 and 5 million variants, determining which variants are clinically significant represents a particular challenge for clinicians.  Clinical geneticists have defined a classification of variants depending on the probability of pathogenicity. 

Researchers at Our Lady’s Children’s Hospital Crumlin and the Children’s University Hospital, Temple Street have completed an international survey of colleagues across different specialties and departments internationally to compare management of patients with class 3 (variants of uncertain significance) or class 4 (likely pathogenic) variants in genes associated with non-syndromic cardiomyopathy or arrhythmia. The electronic survey on clinical management of variants was distributed to colleagues internationally via professional bodies and direct email. Of the 150 respondents (88 centres, 27 countries) who completed the survey, most were Clinical Geneticists or Genetic Counsellors.

Although some variability existed between and within centres and specialties, most respondents (97%) offer pre-symptomatic testing to asymptomatic relatives of an individual with class 4 (likely pathogenic) or class 5 (pathogenic) variants.  A minority of respondents (12%) would offer pre-symptomatic testing for class 3 variants.  There was clear variability in the management of carriers and non-carriers of class 4 variants and there was concern regarding duty to review variants of uncertain significance.

This study demonstrates that variability in management of likely pathogenic/uncertain variants exists and that close multi-disciplinary input is essential. The researchers conclude that the development of disorder or gene-specific evidence-based guidelines might ameliorate uncertainty in management.  They highlight the importance that clinicians consider the possibility of re-interpretation and re-classification of variants when returning results to patients so that patients can be appropriately counselled.  The researchers conclude that standardisation of practice and ongoing intra-departmental and inter-departmental audits of reporting and management of affected families would benefit both patients and clinicians alike an improve confidence in testing.

Original Paper

Managing uncertainty in inherited cardiac pathologies—an international multidisciplinary survey

McVeigh TP, Kelly LJ, Whitmore E, Clark T, Mullaney B, Barton DE, Ward A, Lynch SA.

Eur J Hum Genet. 2019 Apr 12. [link]

Article adapted from paper abstract reproduced with the permission of the senior author.