Exome sequencing of fetal anomaly syndromes: novel phenotype\u2013genotype discoveries

Jürgen Hench,Rabih Chaoui,Sylvia Hoeller,Irene Hoesli,Isabel Filges,Karl Heinimann,Olav Lapaire,Anjeung Kang,Sevgi Tercanli,Elisabeth Bruder,Peter Miny,Julie De Geyter,Nicole Meier

doi:10.1038/s41431-018-0324-y

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.

Highlights

IntroductionA significant proportion of anomaly phenotypes encountered during the antenatal developmental stages may be specific to fetal life since they will lead to embryonic, fetal or perinatal lethality and will have escaped etiological research and clinical delineation so far
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.University Hospital Basel, Basel, Switzerland 5 Department of Obstetrics and Gynecology, University HospitalBasel, Basel, Switzerland 6 Centre for Prenatal Ultrasound, Freie Strasse, Basel, Switzerland 7 Centre for Prenatal Diagnosis, Friedrichstrasse, Berlin, GermanyBirth defects are the leading cause of perinatal lethality in industrialized countries [1]
Variants that were classified to affect or likely affect function were detected in 8 different genes (RYR1, MKS1, FGFR2, PIGW, CENPF, KIF14, SMAD3, and OTX2)

Summary

Introduction

A significant proportion of anomaly phenotypes encountered during the antenatal developmental stages may be specific to fetal life since they will lead to embryonic, fetal or perinatal lethality and will have escaped etiological research and clinical delineation so far They may represent an incomplete or severe allelic presentation of a phenotype described to occur postnatally, and the diagnosis can remain unrecognized at this stage of development. Filges and Friedman [5] stressed the value of applying genomic sequencing to examine such rare extreme phenotypes despite the challenges to expect when interpreting the clinical significance of variants and proving their causality Based on these considerations we explored the clinical and molecular diagnosis using ES in a series of 19 families with one or more fetuses with severe structural anomalies. We aimed at identifying causal as well as candidate variants, showing the utility of ES for diagnosis and discovery, and sought to contribute to the further delineation and etiology of phenotype presentations of known and novel multiple congenital anomaly syndromes in fetal stages intending to increase the yield of future prenatal diagnostic ES

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Conclusion