Genetic counselors and congenital heart disease: Clinical roles, genetic testing practices, and perceived genetic testing utility.

Genetic counseling and genetic testing are essential for individuals with congenital heart disease/defects (CHD/CHDs). However, the clinical practices of genetic counselors (GCs) and their preferences for different CHD genetic testing strategies are previously unexplored. To address these gaps, GCs (n = 112) representing diverse specialties completed an online survey regarding their counseling and testing practices for syndromic CHD and apparently isolated/non-syndromic CHDs (iCHD). We found practice variability around family screening recommendations, with prenatal respondents reporting lower prevalence of this practice for iCHDs (p = 0.0004). We found that all specialties considered chromosomal microarray (CMA) the most common prioritized genetic test for syndromic and iCHD, while more prenatal respondents considered FISH and karyotype useful for iCHDs compared to postnatal respondents (p = 0.0002 and p = 0.002, respectively). Among postnatal respondents, a higher proportion considered exome/genome sequencing as useful compared to prenatal respondents (p = 0.0159); specifically, postnatal respondents' preference for exome/genome sequencing for iCHDs was ~2.6-fold higher than prenatal respondents. We estimated participants' assessment of utility for different genetic testing modalities for iCHDs and found that prenatal respondents assigned higher mean utility to FISH (p = 0.0002), karyotype (p = 0.0006), and CMA (p < 0.0001). There were relatively moderate to decreased utility scores for gene panels and exome/genome sequencing for iCHDs compared to cytogenetic testing, across all specialties. Overall, these results provide insight into GC practices and use of various genetic testing strategies for syndromic CHDs and iCHDs. Findings may help inform and/or standardize clinical practices for CHD genetic testing, though additional studies are warranted.

Disruption of FBN1 by an Alu element insertion: A novel genetic cause of Marfan syndrome.

Alu elements are retrotransposons with ubiquitous presence in the human genome that have contributed to human genomic diversity and health. These approximately 300-bp sequences can cause or mediate disease by disrupting coding/splicing regions in the germline, by insertional mutagenesis in somatic cells, and in promoting formation of copy-number variants. Alu elements may also disrupt epigenetic regulation by affecting non-coding regulatory regions. There are increasing reports of apparently sporadic and inherited genetic disorders caused by Alu-related gene disruption, but Marfan syndrome resulting from Alu element insertion has not been previously described. We report a family with classic features of Marfan syndrome whose previous FBN1 genetic testing was inconclusive. Using contemporary next-generation sequencing and bioinformatics analysis, a pathogenic/disruptive Alu insertion occurring in the coding region of the FBN1 gene was identified (c.6564_6565insAlu; p. Glu2189fs) and was confirmed and specified further with Sanger sequencing. This identified the molecular basis of disease in the family that was missed using previous genetic testing technologies and highlights a novel pathogenic mechanism for Marfan syndrome. This case adds to the growing literature of Mendelian diseases caused by Alu retrotransposition, and it also shows the growing capability of genomic technologies for detecting atypical mutation events.