Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing

Abstract

Purpose: Mendelian phenotypes in humans vary from benign variants to lethal disorders. Embryonic lethal phenotypes that are similar to what has been known for a long time in mice have remained largely unknown because of the difficulty in arriving at a molecular diagnosis. The purpose of this study is to test whether next generation sequencing can reveal the underlying etiology of recurrent fetal loss.

Methods: We hypothesized that exome sequencing combined with autozygome analysis can reveal the underlying mutation in a family in which recurrent fetal loss was likely to be autosomal recessive in origin.

Results: A novel mutation in CHRNA1 was identified. This gene is known to cause multiple pterygium and fetal akinesia syndrome.

Conclusion: This is the first report of exome sequencing to identify the cause of recurrent fetal loss and reveal the diagnosis of a lethal human phenotype. Our results should inspire a systematic examination of the extent of "unborn" Mendelian phenotypes in humans using next-generation sequencing.

Figure 1

Identification of a Mendelian cause of recurrent fetal loss by exome sequencing. (a) Schematic of CHRNA1 protein with the novel mutation indicated by an inverted red triangle. Sequence chromatogram of the fetus and the carrier parent is shown to the right. (b) R254 is strongly conserved in CHRNA1 orthologs. (c) R254 is also conserved across other human CHRN proteins.