Exome Sequencing of Fetal Anomaly Syndromes: Novel Phenotype-genotype Discoveries

Overview

Journal Eur J Hum Genet

Specialty Genetics

Date 2019 Jan 26

PMID 30679815

Citations 24

Authors

Nicole Meier

Elisabeth Bruder

Olav Lapaire

Irene Hoesli

Anjeung Kang

Jurgen Hench

Sylvia Hoeller

Julie De Geyter

Peter Miny

Karl Heinimann

Rabih Chaoui

Sevgi Tercanli

Isabel Filges

Affiliations

Soon will be listed here.

Abstract

The monogenic etiology of most severe fetal anomaly syndromes is poorly understood. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. We employed ES in a cohort of 19 families with one or more fetuses presenting with a distinctive anomaly pattern and/or phenotype recurrence at increased risk for lethal outcomes. Candidate variants were identified in 12 families (63%); in 6 of them a definite diagnosis was achieved including known or novel variants in recognized disease genes (MKS1, OTX2, FGFR2, and RYR1) and variants in novel disease genes describing new fetal phenotypes (CENPF, KIF14). We identified variants likely causal after clinical and functional review (SMAD3, KIF4A, and PIGW) and propose novel candidate genes (PTK7, DNHD1, and TTC28) for early human developmental disease supported by functional and cross-species phenotyping evidence. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. The diagnostic yield of the future application of prenatal ES will depend on our ability to increase our knowledge on the specific phenotype-genotype correlations during fetal development.

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