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

backgroundAutosomal 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.

methodsWhole-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.

resultsWe 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.

conclusionThe 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.