Expanding the genetic spectrum of autosomal recessive microcephaly in Pakistani families.

Authors

Bilal Ahmad, Matthew Adams, Iram Javed, Muhammad Tariq, Anees Muhammad, Laura Harrold, Rebecca J Almond, Nishanka Ubeyratna, Muhammad Tahir Sarwar, Joseph S Leslie, Andrew H Crosby, Emma L Baple, Lettie E Rawlins, Muhammad Qasim

Published in

BMC neurology. Jun 05, 2026. Epub Jun 05, 2026.

Abstract

Autosomal recessive microcephaly encompasses a group of rare neurogenetic disorders in which microcephaly presents at birth or postnatally as part of a syndromic disorder. Autosomal recessive microcephaly is both clinically and genetically heterogeneous, with numerous genes associated. In the present study, we investigated the genetic basis of likely autosomal recessive microcephaly in a cohort of five unrelated consanguineous and non-consanguineous Pakistani families presenting with microcephaly, intellectual disability, and developmental delay.
Whole-exome sequencing was performed on one affected individual from each family. Candidate variants identified by WES were subsequently validated by Sanger sequencing, and segregation analysis was performed in all available affected and unaffected family members.
We identified five homozygous pathogenic variants, including three novel variants: ASPM (NM_018136.5:c.1669_1670del p.(Ser557Leufs*2)), CDK5RAP2 (NM_018249.6:c.199del p.(Ile67Serfs*4)), and VPS13B (NM_152564.5:c.8230 C > T (p.Gln2744*)). Alongside, two previously reported homozygous variants in ASPM (NM_018136.5:c.9190 C > T p.(Arg3064*) & NM_018136.5:c.3978G > A p.(Trp1326*)). All variants matched a suspected autosomal recessive inheritance pattern, segregated within their respective families, and were absent or very rare in proxy population genetic databases.
The results expand the genetic spectrum of autosomal recessive microcephaly within the Pakistani population and highlight the importance of whole exome sequencing in diagnosing rare neurodevelopmental disorders and understanding genetic diversity.

PMID:
42249392
Bibliographic data and abstract were imported from PubMed on 06 Jun 2026.

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