Gene Discovery in Lethal Foetal Disorders

Abstract

Prenatal ultrasonography identifies an increasing number of foetal malformation phenotypes of unknown cause. For a significant number of these often lethal phenotypes, the underlying causal mutations are not identified yet, but animal data predict that up to 30% of the protein‐coding genes of our genome are implicated in embryonic development. Little attention has been paid to gene identification in these disorders, which often may present with a specific but so far unrecognised phenotype during foetal life. Counselling in prenatal diagnosis clinics to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory. Next‐generation sequencing offers unprecedented opportunities and perspectives to unravel the Mendelian basis of foetal disorders. Key Concepts Malformations and genetic disorders are the leading cause of infant mortality in the developed countries accounting for more than one third of cases. Foetal structural anomalies, often serious or lethal and of unknown cause despite current diagnostic genetic testing available, are increasingly identified at earlier gestational ages due to advancing ultrasound techniques. Counselling to inform prognosis and management decisions but also recurrence risk in these situations remains unsatisfactory. By identification of rare variants through whole exome or genome sequencing, many mutations in additional genes have been discovered to cause postnatal disease phenotypes. Next‐generation sequencing technologies have rarely been used to discover genes in which mutations cause early embryonic and foetal maldevelopment. On the basis of analysis of knockout and spontaneous mouse models, loss‐of‐function variants in up to 30% of genes could result in embryonic lethality in humans. Studying genes implicated in embryonic and foetal development and their phenotypes reveals important biological information on early errors in human morphogenesis and will contribute to annotate the function of relevant protein‐coding genes in our genome. Reliable applications of NGS strategies in future prenatal diagnosis will depend on our knowledge on specific foetal genotype–phenotype correlations.