Whole Exome Sequencing Identifies Three Novel Mutations in the ASPM Gene From Saudi Families Leading to Primary Microcephaly.

Muhammad Imran Naseer,Adeel G Chaudhary,Sameera Sogaty,Sarah Almaghrabi,Osama Yousef Muthaffar,Angham Abdulrahman Abdulkareem,Hiba Alkhatabi

doi:10.3389/fped.2020.627122

Muhammad Imran Naseer, Adeel G Chaudhary + Show 5 more

Open Access

https://doi.org/10.3389/fped.2020.627122

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Abstract

Autosomal recessive primary microcephaly (MCPH) is a neurodevelopmental defect that is characterized by reduced head circumference at birth along with non-progressive intellectual disability. Till date, 25 genes related to MCPH have been reported so far in humans. The ASPM (abnormal spindle-like, microcephaly-associated) gene is among the most frequently mutated MCPH gene. We studied three different families having primary microcephaly from different regions of Saudi Arabia. Whole exome sequencing (WES) and Sanger sequencing were done to identify the genetic defect. Collectively, three novel variants were identified in the ASPM gene from three different primary microcephaly families. Family 1, showed a deletion mutation leading to a frameshift mutation c.1003del. (p.Val335*) in exon 3 of the ASPM gene and family 2, also showed deletion mutation leading to frameshift mutation c.1047del (p.Gln349Hisfs*18), while in family 3, we identified a missense mutation c.5623A>G leading to a change in protein (p.Lys1875Glu) in exon 18 of the ASPM gene underlying the disorder. The identified respective mutations were ruled out in 100 healthy control samples. In conclusion, we found three novel mutations in the ASPM gene in Saudi families that will help to establish a disease database for specified mutations in Saudi population and will further help to identify strategies to tackle primary microcephaly in the kingdom.

Highlights

Primary microcephaly (MCPH, OMIM 251200) is a congenital genetic neurodevelopmental disorder characterized by a small brain size along with mild to moderate intellectual disability
We identified three families having novel variants in the ASPM gene that will be helpful for geneticists and clinicians to establish reliable diagnostic strategies for primary microcephaly families in Saudi population
We did not find any homozygous mutation or heterozygous mutation in the family, but after applying various tools, the results showed a missense mutation c.5623A>G leading to a change in protein p.Lys1875Glu in exon 18 of the ASPM gene related to primary microcephaly

Summary

Introduction

Primary microcephaly (MCPH, OMIM 251200) is a congenital genetic neurodevelopmental disorder characterized by a small brain size along with mild to moderate intellectual disability. Most of the patients have normal height, weight, and physical appearance as well as chromosomal banding pattern and brain scan result. Mutations in ASPM Gene Causing Microcephaly show abnormal chromosomal analysis and short stature with mild to severe intellectual disability [1, 4]. Studies on brain growth revealed that primary microcephaly is due to the abnormal developmental process and not because of the degeneration or regression of the neuronal tissues [5, 6]. In the OMIM gene database, 25 genes associated with primary microcephaly have been reported so far

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