Screening Pathogenic Genes For Human Microcephaly Using Whole-Exome Sequencing

Microcephaly(MCPH)is a kind of neurodevelopmental disorder based on autosomal recessive genetic pattern,which is often seen in the offspring of consanguineous marriage.Compared with the same age,gender and race people,the occipito frontal head circumference(OFC)of the patients is 2-3 standard deviations(SDS)lower at birth,and the volume and surface area of the cerebral cortex are obviously smaller.The patients have a certain degree of intellectual disability,hyperactivity disorder,expressive language disorders,epilepsy and some other mental disorders.The pathogenic factors of microcephaly include genetic and environmental factors,and there are 18 genes related to microcephaly reported at present.With the development of next generation sequencing technology,more related genes and variations will be found.In this study,DNA samples from two families of Pakistani patients were detected by whole-exome sequencing(WES),and the new pathogenic variation of ASPM(c.77 delG,p.G26fs)/NDE1(c.728 delC,p.T243fs)was found and confirmed by Sanger sequencing.Furthermore,we predicted the structure of ASPM and NDE1 mutation protein,and we found that ASPM mutation resulted in the generation of truncated protein,while NDE1 mutation resulted in the change of protein sequence,these may be the main causes of microcephaly.This study complements the reported pathogenic variation of microcephaly,and provides a new idea for the application of whole-exome sequencing in disease diagnosis,especially in prenatal diagnosis.