Homozygous Nonsense Mutation in SCHIP1/IQCJ-SCHIP1 Causes a Neurodevelopmental Brain Malformation Syndrome

We report a consanguineous Arab family with three affected siblings who display a disorder of global developmental delay, learning difficulties, facial dysmorphism, hearing impairments, and cataract. The clinical phenotype was associated with characteristic brain Magnetic Resonance Imaging (MRI) features of axonal guidance defects involving anterior commissure agenesis as well as scattered areas of polymicrogyria-cobblestone complex. Whole genome sequencing revealed a novel nonsense mutation (159609921C>T) that segregated in the family consistent in an autosomal recessive pattern. This mutation located in the C-terminal region shared by the Schwanomin-Interacting Protein1 (SCHIP1) isoforms including the IQCJ-SCHIP1. The in-vitro expression of SCHIP1 and IQCJ-SCHIP1 truncated mutant isoforms (NM_001197109.1; p.R209* and NM_001197114.1; p.R501*, respectively) were markedly reduced as compared to their full-length versions suggesting protein stability/folding impairment. The pathogenic nature of this mutation is supported by a previously reported mouse knockout of Schip1 isoforms, which phenocopied the human axon guidance abnormality. This is the first report of a SCHIP1/IQCJ-SCHIP1 point mutation in humans associated with a neurological-developmental phenotype.

Three siblings of a consanguineous parent with developmental delay, hearing loss, cataract, axonal guidance defects & Polymicrogyria.

Genomic organization of the SCHIP1/IQCJ-SCHIP1 isoforms with the nonsense mutation located at the C-terminal region common to all isoforms

Significant wide homozygosity blocks on chromosome 3 encompassing SCHIP1/ IQCJ-SCHIP1 locus supports the data analysis of whole genome sequencing

Sanger sequence validated the recessive segregation of this nonsense mutation in SCHIP1/IQCJ-SCHIP1.

from Genetics via xlomafota13 on Inoreader http://ift.tt/2ulDSE9
via IFTTT