Elucidating the Genetic Landscape, Phenotypic Spectrum, and Pathogenic Mechanisms in a Turkish Cohort with Primary Microcephaly

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Primary hereditary microcephaly (MCPH) comprises a group of genetically heterogeneous disorders characterized by severe microcephaly and mild intellectual disability. It differs from syndromic primary microcephaly (PM) by the lack of syndromic features and major brain malformations. We evaluated the genetic diagnostic yield, pathogenic mechanisms, and clinical features of these two PM groups in 87 patients from 64 families. Exome sequencing was performed on probands, 52 of whom had consanguineous parents. The diagnostic yield was 53.1%. Of the 34 disease-causing variants identified, 15 were novel, with 83.7% being biallelic. MCPH-associated genes were found in 17.2% of families, while syndromic PM accounted for 35.9%. Most patients in both groups had speech delay. In the MCPH group, borderline to mild intellectual disability, independent of microcephaly severity, and behavioral abnormalities were prominent, whereas severe intellectual disability was more common in the syndromic group. Notably, most genes associated with MCPH are involved in mitotic division and DNA repair pathways, while those in syndromic PM are involved in transcription regulation and cell trafficking pathways. A bird-like facial gestalt was observed in patients from both groups with genes related to mitotic division and DNA repair. In addition, we expanded the genetic heterogeneity to include a potential candidate gene, KNTC1.