Genetic variants in childhood-onset dilatation of thoracic aorta in a consanguineous population

Abstract

Introduction: Childhood-onset thoracic aortic dilatation (TAD) is a heterogenous group of genetic conditions the inheritance of which is largely dominant. To our knowledge, the influence of consanguinity on childhood-onset TAD has not been addressed systematically. We aim to study a cohort of children with TAD in our highly consanguineous population.

Methods: Children with TAD were consecutively recruited. Based on the likelihood of a founder mutation, genetic test was categorized to either targeted gene testing or multi-gene sequencing, followed by genetic screening of first-degree relatives. Clinical data and outcome were reviewed.

Results: Thirty-three children, from 20 families, had childhood-onset TAD. Genetic test was positive in 20 children, from 13 families, providing a yield of 65 % (13/20). The median age of onset of TAD was 4.5 years. Eight variants were detected in 4 genes (FBN1, EFEMP2, ACTA2, KANSL1) with a homozygous EFEMP2 variant found in 6 families (46.2 %). Surgical intervention was required in 14 (70 %) cases (13 with EFEMP2, 1 with FBN1 variants) at a median age of 3.5 years. All patients are alive (ages range:3-31 years).

Conclusions: Our work illustrates the impact of consanguinity on the genetics of childhood-onset TAD elucidating severe presentation of recessively inherited form. Our data underscores the importance of genetic screening and early recognition of TAD to achieve excellent outcome.

Keywords: Childhood TAD; Consanguinity; Founder mutation; Whole exome sequencing.