Exome sequencing for gene discovery in lethal fetal disorders – harnessing the value of extreme phenotypes

Abstract

Massively parallel sequencing has revolutionized our understanding of Mendelian disorders, and many novel genes have been discovered to cause disease phenotypes when mutant. At the same time, next-generation sequencing approaches have enabled non-invasive prenatal testing of free fetal DNA in maternal blood. However, little attention has been paid to using whole exome and genome sequencing strategies for gene identification in fetal disorders that are lethal in utero, because they can appear to be sporadic and Mendelian inheritance may be missed. We present challenges and advantages of applying next-generation sequencing approaches to gene discovery in fetal malformation phenotypes and review recent successful discovery approaches. We discuss the implication and significance of recessive inheritance and cross-species phenotyping in fetal lethal conditions. Whole exome sequencing can be used in individual families with undiagnosed lethal congenital anomaly syndromes to discover causal mutations, provided that prior to data analysis, the fetal phenotype can be correlated to a particular developmental pathway in embryogenesis. Cross-species phenotyping allows providing further evidence for causality of discovered variants in genes involved in those extremely rare phenotypes and will increase our knowledge about normal and abnormal human developmental processes. Ultimately, families will benefit from the option of early prenatal diagnosis.

Comprehensive Analysis of Tissue-wide Gene Expression and Phenotype Data Reveals Tissues Affected in Rare Genetic Disorders

“…For instance, genes that regulate body weight do not necessarily regulate energy metabolism or pathways in adipose tissue but rather exert an effect through altered activity in brain (Locke et al, 2015). Lastly, severe disease-causing genetic variants and associated genes are absent in genetic disorder databases due to embryonic lethality and low fitness (Filges and Friedman, 2015). These limitations suggest future directions for sample collection and measurement to enhance the links between genetic variants and their clinical manifestations.…”

Genomic analysis in the clinic: benefits and challenges for health care professionals and patients in Brazil

“…For instance, excellent results have been obtained with WES/WGS for investigation of seemingly genetic disorders that present with atypical manifestations, are difficult to confirm using simple clinical or laboratory criteria or otherwise require extensive or costly evaluation; these are usually disorders with high clinical and genetic heterogeneity, such as intellectual disability, congenital malformations and mitochondrial dysfunctions (Need et al 2012;Dixon-Salazar et al 2012;Pinxten and Howard 2014). Usage of WES/WGS in cancer genetics and prenatal diagnosis is less favourable (GraciaAznarez et al 2013;Filges and Friedman 2014). This is reflected in practical terms in the proportion of different subspecialties requesting genomic testing in the clinic.…”

Recent advances in prenatal genetic screening and testing

“…With recent technological advances in methods to identify numerical and structural chromosome abnormalities and point mutations, such as array-based copy-number analysis, also known as chromosomal microarray analysis (CMA), and next-generation sequencing (NGS), the screening for and diagnosis of genetic abnormalities in the fetus is undergoing an unprecedented rapid evolution 4– 13 . In parallel, CMA and NGS have also accelerated the discovery of causes of intellectual disability, birth defects, and many rare genetic and genomic disorders 14– 17 .…”