Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound

Keren J. Carss, Sarah C. Hillman, Vijaya Parthiban, Dominic J. McMullan, Eamonn R. Maher, Mark D. Kilby*, Matthew E. Hurles

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants( CNVs),whichcollectively yield a pathogenic finding inupto10%of cases.We propose thatexomesequencing may substantially increase the identification of underlying etiologies.Weperformed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information.We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing.

Original languageEnglish
Pages (from-to)3269-3277
Number of pages9
JournalHuman Molecular Genetics
Issue number12
Early online date29 Jan 2014
Publication statusPublished - 15 Jun 2014


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