When genetic burden reaches threshold

Abstract

Rare cardiac genetic diseases have generally been considered to be broadly Mendelian in nature, with clinical genetic testing for these conditions predicated on the detection of a primary causative rare pathogenic variant that will enable cascade genetic screening in families. However, substantial variability in penetrance and disease severity among carriers of pathogenic variants, as well as the inability to detect rare Mendelian variants in considerable proportions of patients, indicates that more complex aetiologies are likely to underlie these diseases. Recent findings have suggested genetic variants across a range of population frequencies and effect sizes may combine, along with non-genetic factors, to determine whether the threshold for expression of disease is reached and the severity of the phenotype. The availability of increasingly large genetically characterized cohorts of patients with rare cardiac diseases is enabling the discovery of common genetic variation that may underlie both variable penetrance in Mendelian diseases and the genetic aetiology of apparently non-Mendelian rare cardiac conditions. It is likely that the genetic architecture of rare cardiac diseases will vary considerably between different conditions as well as between patients with similar phenotypes, ranging from near-Mendelian disease to models more akin to common, complex disease. Uncovering the broad range of genetic factors that predispose patients to rare cardiac diseases offers the promise of improved risk prediction and more focused clinical management in patients and their families.

Novel SCN5A p.Val1667Asp Missense Variant Segregation and Characterization in a Family with Severe Brugada Syndrome and Multiple Sudden Deaths

“…Despite the recent literature discussing whether BrS is a far more complex disorder [ 13 , 14 ], it has been historically believed to be a Mendelian disease, caused by a single mutation in a single gene. Variants detected in BrS patients have more often been described in SCN5A than in any other gene [ 4 ] and for this reason, some of them have been described as a monogenic cause of BrS.…”

Opportunistic genomic screening. Recommendations of the European Society of Human Genetics

“…Also, ACMG underlines the importance of ongoing research into penetrance and expression (range of severity) [26]. Clearly, the penetrance of some of the variants in genes on the ACMG list has been overestimated [32][33][34]. Given that OGS is offered to individuals that do not have a higher a priori risk than the general population with regard to the SFs on the list, penetrance figures based on data from affected families may overestimate their risk of actually developing the disorder [35].…”

Phenotypic variability and modifier variants in children with hereditary heart diseases

“…генетические варианты с промежуточным эффектом и относительно небольшой частотой в популяции (MAF <1%). Именно для них была показана различная степень влияния на пенетрантность у пациентов с моногенными болезнями [5,15]. Эти варианты, вероятно, вносят вклад в риск развития заболевания у людей как с патогенными каузативными вариантами, так и в их отсутствие.…”

“…В настоящее время анализ данных высокопроизводительного секвенирования нового поколения уже практически стал стандартом клинического обследования таких пациентов [4]. Одно из важных преимуществ этой диагностики -выявление в семьях пробандов с патогенным нуклеотидным вариантом, приведшим к заболеванию, бессимптомных (малосимптомных) носителей этого патогенного варианта и лиц, не являющихся носителями, у которых не разовьется данное заболевание [5].…”