PDCD6IP, encoding a regulator of the ESCRT complex, is mutated in microcephaly

Abstract

Primary microcephaly (PM) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes and loci identified to date. We report a consanguineous family with PM, intellectual disability and short stature. Using whole exome sequencing, we identified a homozygous frameshift variant in programmed cell death 6 interacting protein (PDCD6IP, c.154_158dup; p.Val54Profs*18). This gene, PDCD6IP, plays an important role in the endosomal sorting complexes required for transport (ESCRT) pathway in the abscission stage of cytokinesis and apoptosis, and is required for normal brain development in mice. The clinical features observed in our patient were similar to the phenotypes observed in mouse and zebrafish models of PDCD6IP mutations in previous studies. This study provides evidence that clinical manifestations of PDCD6IP mutations as seen in our patients with PM and ID may be a novel cause for neurodevelopmental disorders.

Keywords: PDCD6IP; consanguineous family; intellectual disability; microcephaly; whole exome sequencing.

FIGURE 1

A, Pedigree of the present family. B, Sanger sequence chromatograms of the affected individuals (upper panel) or heterozygous carriers (lower panel) with PDCD6IP mutations. C, MRI of the proband, Sagittal T1-WI (I) shows microcephaly. Axial T1-WI and T2-WI (II, III) demonstrate a mildly simplified gyral pattern with normal cortical thickness. Axial T2-WI (IV) shows a disproportionally large cerebellum. D, Schematic representation of all 20 exons of the PDCD6IP gene. E, Known three structural and functional domains (Bro 1, V and Proline rich) of the mature PDCD6IP protein. Arrows show the position of the mutation (c.154_158dup; p.Val54Profs*18) identified in this study