Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability.

Publisher: Springer-Verlag Country of Publication: United States NLM ID: 9709714 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1364-6753 (Electronic) Linking ISSN: 13646745 NLM ISO Abbreviation: Neurogenetics Subsets: MEDLINE

Publication: <2002->: [New York, N.Y.?] : Springer-Verlag
Original Publication: Oxford, UK : Oxford University Press, c1997-

Microcephaly*/genetics ; Intellectual Disability*/genetics ; Cell Cycle Proteins*/genetics ; Pedigree*; Humans ; Male ; Female ; Adult ; Chromosomal Proteins, Non-Histone/genetics ; Nerve Tissue Proteins/genetics ; Cell Division/genetics ; Mutation ; Intracellular Signaling Peptides and Proteins/genetics ; Genomics ; Young Adult ; Consanguinity ; Exome Sequencing ; Homozygote ; Developmental Disabilities/genetics ; Adolescent ; Pakistan ; Microtubule-Associated Proteins

Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.
(© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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Keywords: Consanguineous families; Primary microcephaly; WES, CENPJ, STIL, CDK5RAP2, RBBP8; and CEP135 variants

0 (Cell Cycle Proteins)
0 (CENPJ protein, human)
0 (STIL protein, human)
0 (Chromosomal Proteins, Non-Histone)
0 (Nerve Tissue Proteins)
0 (CDK5RAP2 protein, human)
0 (Intracellular Signaling Peptides and Proteins)
0 (Microtubule-Associated Proteins)

Date Created: 20240525 Date Completed: 20240715 Latest Revision: 20240715

20240715

10.1007/s10048-024-00759-7

38795246