Blue, Gillian M and Humphreys, David and Szot, Justin and Major, Joelene and Chapman, Gavin and Bosman, Alexis and Kirk, Edwin P and Sholler, Gary F and Harvey, Richard P and Dunwoodie, Sally L and Winlaw, David S (2017) The promises and challenges of exome sequencing in familial, non-syndromic congenital heart disease. International Journal of Cardiology, 230. pp.155-163. ISSN 1874-1754 (PP OA)
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Abstract
BACKGROUND
Exome sequencing is an established strategy to identify causal variants in families with two or more members affected by congenital heart disease (CHD). This unbiased approach, in which both rare and common variants are identified, makes it suitable to research complex, heterogeneous diseases such as CHD.
METHODS AND RESULTS
Exome sequencing was performed on two affected members of a three generation family with atrial septal defects (ASD), suggesting a dominant inheritance pattern. Variants were filtered using two bioinformatics pipelines and prioritised according to in silico prediction programs. Segregation studies and functional analyses were used to assess co-segregation with disease and effects on protein function, respectively. Following the data and in silico analyses, ten candidate variants were prioritised. Of these, SRPK2 (c.2044C>T[p.Arg682Trp]) and NOTCH1 (c.3835C>T[p.Arg1279Cys]), co-segregated with disease in the family; however, previous functional analyses on SRPK2 make this an unlikely candidate. Functional analyses in the variant (c.3835C>T[p.Arg1279Cys]) of the known CHD gene NOTCH1 demonstrated a non-significant decrease in signalling activity.
CONCLUSION
This study demonstrates both the potential, as well as the challenges, of applying exome sequencing to complex diseases such as CHD. While in silico evidence and segregation analyses in the NOTCH1 p.Arg1279Cys variant are highly suggestive of pathogenicity, the minimal change in signalling capacity suggests that other variants may be required for CHD development. This study highlights the difficulties of applying exome sequencing in familial, non-syndromic CHD in the clinical environment and a cautionary note in the interpretation of apparently causal abnormalities in silico without supportive functional data.
| Item Type: | Article |
|---|---|
| Additional Information: | ePub 2016 |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 20 Dec 2016 23:59 |
| Last Modified: | 15 Jan 2018 00:44 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/527 |
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