![]() After written informed consent for participation was obtained from the parents, we prospectively recruited 19 families-26 fetuses (after fetal or perinatal death or from terminated pregnancies) and one child-that presented with severe anomalies of unexplained etiology initially identified by ultrasound scanning. The study was approved by the Ethics Commission Northwest Switzerland (EKNZ 2014-174). We aimed at identifying causal as well as candidate variants, showing the utility of ES for diagnosis but also 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. 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. Filges and Friedman 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. They may also represent an incomplete or severe allelic presentation of a phenotype described to occur postnatally, and the diagnosis therefore can remain unrecognized at this stage of development. However, 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. In general, the diagnostic yield seems to be higher in fetuses with multiple congenital anomalies and in selected series with detailed clinical genetics review. Approaches in such studies are highly heterogeneous ranging from prospective prenatal ES to the study of selected cases with severe fetal anomalies after termination or stillbirth. discussed its promises and pitfalls including the review of 31 studies with series of five or more fetuses and diagnostic rates varying between 6.2% and 80%. Only recently, however, the delineation of fetal anomaly phenotypes received increasing attention including the discussion of introducing exome sequencing (ES) in standard prenatal care. Exome or genome approaches have now become available in routine clinical genetics services for the diagnosis of patients with developmental disorders. ![]() The monogenic etiology of phenotypes observed postnatally has been successfully investigated by using genome-wide sequencing technologies. Targeted molecular testing may be indicated if a specific monogenic entity is suspected based on clinical signs. Prenatal high-resolution chromosomal microarray analysis will allow a diagnosis of causal copy number variants in up to additional 10% of pregnancies after the exclusion of the frequent aneuploidies, but 80–90% of families remain without definite diagnosis. ![]() With the advance of high-resolution ultrasound fetal structural anomalies are now detected increasingly early during pregnancy, raising questions about diagnosis, etiology, prognosis, and recurrence risk for parents and health care providers, particularly in the presence of more than one fetal anomaly likely indicating a congenital malformation syndrome. 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.īirth defects are the leading cause of perinatal lethality in industrialized countries. We describe rare and novel fetal anomaly syndromes and highlight the diagnostic utility of ES, but also its contribution to discovery. 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. 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 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. Our objective was to use exome sequencing (ES) to increase our knowledge on causal variants and novel candidate genes associated with specific fetal phenotypes. The monogenic etiology of most severe fetal anomaly syndromes is poorly understood.
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