The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects.

Am J Med Genet A. 2015 Aug;167(8):1822-9. doi: 10.1002/ajmg.a.37108. Epub 2015 Apr 30.

The diagnostic value of next generation sequencing in familial nonsyndromic congenital heart defects.

Jia Y1Louw JJ1,2Breckpot J1,3Callewaert B4Barrea C5Sznajer Y6Gewillig M2Souche E1Dehaspe L1Vermeesch JR1Lambrechts D7,8Devriendt K1,Corveleyn A1.

Comment: Jia and colleagues sought to identify disease-causing genetic variants from families with nonsyndromic cardiovascular malformations (CVMs). In total 13 families, each containing at least 3 relatives (1st or 2nd degree) with a CVM, were recruited from clinics in Belgium. Subjects were tested for coding or splice variants from a customized panel of 57 genes that are already known to be associated with syndromic or nonsyndromic CVMs (e.g. JAG1, NKX2-5). The study included relatives with and without CVMs as confirmed by echocardiography. Among the 36 subjects tested with the 57-gene panel, there were 44 heterozygous rare variants (i.e. variants present in less than 1% of individuals in large reference population databases). Based on bioinformatics-based predictions of the effect of these variants and segregation with disease within families, the authors concluded that a heterozygous variant likely to be causing CVMs was identified in 6 of the 13 families (46%) in autosomal dominant inheritance patterns. Three families carried variants in NOTCH1 (one missense, one frameshift, one splice donor site), 2 families carried variants in TBX5 (both missense), and 1 family carried a variant in MYH6 (missense). One of the TBX5 variants was previously reported, but the other 5 variants were novel.

There are several aspects of the study’s findings that highlight the complex nature of the genetics of nonsyndromic CVMs. First, in at least 3 of the 6 families there were individuals who carried the suspected causative variant but who had normal cardiac anatomy (i.e. reduced penetrance). Second, in 2 of the 6 families there were individuals with a CVM who did not carry the variant suspected to be causative within the family; the authors speculate that the relatively high prevalence of CVMs overall can lead to instances where even related individuals have different genetic mechanisms. These observations emphasize the importance of testing as many relatives as possible both in research and clinical settings. Third, the specific type of CVM often varied significantly within families (i.e. intra-familial variable expression). Finally, the subjects with TBX5 variants did not demonstrate the upper limb skeletal malformations classically associated with Holt-Oram syndrome. This raises the possibility that mutation testing for this gene may be informative in nonsyndromic TAA rather than only in cases of CVMs and upper limb malformations. Continued advancement of our understanding of the genetic mechanisms of familial CVMs will require functional interpretation of variants as well as integration of various classes of human genetic variation. These data are critical as broad gene panels and whole exome/genome sequencing testing become increasingly available clinically.