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

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.

Automated Prioritization of Sick Newborns for Whole Genome Sequencing Using Clinical Natural Language Processing and Machine Learning

“…We validated the results presented below using leave-one-out cross validation; see methods for details. To examine the broader applicability of the RCHSD training data to other NICUs, we also carried out a second independent, retrospective validation study using the clinical notes and diagnoses for the 36 WGS probands sequenced to date by the University of Utah NeoSeq program 15 .…”

“…In total, the RCHSD dataset consisted of 1049 individuals. A second independent dataset of 35 probands that were sequenced as part of the University of Utah NeoSeq program 15 and 2930 randomly selected University of Utah Level-III NICU patients from 2010 to 2022, was retrospectively analyzed to evaluate the utility of the RCHSD training data for prioritizing probands for rWGS at a second institution.…”

“…We also carried out a second independent replication study using the clinical notes of 2965 University of Utah Level-III NICU admits. This dataset includes 35 WGS probands sequenced to date by the University of Utah NeoSeq program 15 .…”

“…All performance metrics were computed using this cross-validation scheme. We also carried out a second independent, retrospective validation study using the clinical notes and diagnoses for the 36 WGS probands sequenced to date by the University of Utah NeoSeq program 15 .…”

Annotation of structural variants with reported allele frequencies and related metrics from multiple datasets using SVAFotate

“…A primary motivation for developing SVAFotate was to enable filtering of SV calls using known population AFs. We further demonstrate the use of SVAFotate annotations by applying them to rare disease cases from the Utah NeoSeq Project (27), a rapid WGS protocol to provide genetic diagnoses for critically ill infants in the University of Utah Hospital neonatal intensive care unit. Since the inception of the Utah NeoSeq Project, SVAFotate has been used in the SV analysis and prioritization pipeline.…”