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Research: Comprehensive variant calling from whole-genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

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Research: Comprehensive variant calling from whole-genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

Mol Genet Genomic Med

. 2022 Feb 4;e1888. doi: 10.1002/mgg3.1888. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/35119225/

Comprehensive variant calling from whole-genome sequencing identifies a complex inversion that disrupts ZFPM2 in familial congenital diaphragmatic hernia

Thomas J Nicholas 1Najla Al-Sweel 2 3Andrew Farrell 1Rong Mao 2 3Pinar Bayrak-Toydemir 2 3Christine E Miller 2Dawn Bentley 4Rachel Palmquist 5 6Barry Moore 1Edgar J Hernandez 1Michael J Cormier 1Eric Fredrickson 2Katherine Noble 2Shawn Rynearson 1Carson Holt 1Mary Anne Karren 1Joshua L Bonkowsky 5 6Martin Tristani-Firouzi 7Mark Yandell 1Gabor Marth 1Aaron R Quinlan 1 8Luca Brunelli 4Reha M Toydemir 2 3Brian J Shayota 9John C Carey 9Steven E Boyden 1Sabrina Malone Jenkins 4Affiliations expand

Free article

Abstract

Background: Genetic disorders contribute to significant morbidity and mortality in critically ill newborns. Despite advances in genome sequencing technologies, a majority of neonatal cases remain unsolved. Complex structural variants (SVs) often elude conventional genome sequencing variant calling pipelines and will explain a portion of these unsolved cases.

Methods: As part of the Utah NeoSeq project, we used a research-based, rapid whole-genome sequencing (WGS) protocol to investigate the genomic etiology for a newborn with a left-sided congenital diaphragmatic hernia (CDH) and cardiac malformations, whose mother also had a history of CDH and atrial septal defect.

Results: Using both a novel, alignment-free and traditional alignment-based variant callers, we identified a maternally inherited complex SV on chromosome 8, consisting of an inversion flanked by deletions. This complex inversion, further confirmed using orthogonal molecular techniques, disrupts the ZFPM2 gene, which is associated with both CDH and various congenital heart defects.

Conclusions: Our results demonstrate that complex structural events, which often are unidentifiable or not reported by clinically validated testing procedures, can be discovered and accurately characterized with conventional, short-read sequencing and underscore the utility of WGS as a first-line diagnostic tool.

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