Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population.

Niaz Muhammad Khan,Qingquan Gu,Basharat Hussain,Naveed Altaf Malik,Muhammad Qasim,Junlei Chang,Ayaz Khan,Chenqing Zheng,Muhammad Tariq,Muhammad Shareef Masoud,Linhui Qiu

doi:10.3389/fped.2021.695133

Abstract

Microcephaly (MCPH) is a genetically heterogeneous disorder characterized by non-progressive intellectual disability, small head circumference, and small brain size compared with the age- and sex-matched population. MCPH manifests as an isolated condition or part of another clinical syndrome; so far, 25 genes have been linked with MCPH. Many of these genes are reported in Pakistani population, but due to a high rate of consanguinity, a significant proportion of MCPH cohort is yet to be explored. MCPH5 is the most frequently reported type, accounting for up to 68.75% alone in a genetically constrained population like Pakistan. In the current study, whole exome sequencing (WES) was performed on probands from 10 families sampled from South Waziristan and two families from rural areas of the Pakistani Punjab. Candidate variants were validated through Sanger sequencing in all available family members. Variant filtering and in silico analysis identified three known mutations in ASPM, a MCPH5-associated gene. The founder mutation p.Trp1326* was segregating in 10 families, which further confirmed the evidence that it is the most prominent mutation in Pashtun ethnicity living in Pakistan and Afghanistan. Furthermore, the previously known mutations p.Arg3244* and p.Arg1019* were inherited in two families with Punjab ethnic profile. Collectively, this study added 12 more families to the mutational paradigm of ASPM and expanded the Pakistani MCPH cohort.

Highlights

(MCPH, OMIM#251200) is a neurodevelopmental disorder characterized by a small head circumference, nonprogressive intellectual disability, and small brain size compared with the age- and sex-matched population
This study reports on three previously known ASPM variants in 12 Pakistani MCPH families with 34 affected individuals (18 males and 16 females)
The resulting FASTQ files were transformed to BAM, and the BAM files were converted to variant call format file

Summary

INTRODUCTION

(MCPH, OMIM#251200) is a neurodevelopmental disorder characterized by a small head circumference, nonprogressive intellectual disability, and small brain size compared with the age- and sex-matched population. ASPM (MIM# 605481), located on chromosome 1q31.3, is 6.2 kb long with 28 exons, coding for 3,477 amino acids (Ensemble, GRCh38/hg38) This gene plays a vital role in the division of neural progenitor cells and in controlling the cell cycle by helping symmetric proliferative division, as well as asymmetric neurogenic divisions. The other two families are from rural areas of Pakistani Punjab and are mutually unrelated Genetic analysis of these families revealed three known mutations in ASPM, a MCPH5-associated gene. The p.Trp1326∗ variant has been previously reported as a founder mutation in more than 50 families among various Pashtun tribes including Wazir [4, 12] The segregation of this variant in 10 unrelated Wazir families in the current study suggests that this variant represents an old mutation and that mutations in this gene are a rare event

Study Participants and Pedigree Construction

RESULTS

ETHICS STATEMENT