Elucidating the Genetic Landscape, Phenotypic Spectrum, and Pathogenic Mechanisms in a Turkish Cohort with Primary
Beyhan Tüysüz1,2, Ahmet Okay Çağlayan3, Büşra Kasap1
1Cerrahpasa Medical Faculty, Department of Pediatric Genetics, Istanbul University-Cerrahpasa, Istanbul, Turkey.
Abstract:
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.
Insights
This study identifies genetic causes for primary hereditary microcephaly (MCPH) and syndromic primary microcephaly (PM), finding a 53.1% diagnostic yield. Key differences in affected genes and clinical features were observed between MCPH and syndromic PM groups.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Human Molecular Genetics
Background:
- Primary hereditary microcephaly (MCPH) and syndromic primary microcephaly (PM) are distinct neurodevelopmental conditions.
- Understanding their genetic basis is crucial for diagnosis and potential therapies.
Purpose of the Study:
- To determine the genetic diagnostic yield and characterize pathogenic mechanisms and clinical features in MCPH and syndromic PM.
- To differentiate between MCPH and syndromic PM based on genetic and phenotypic data.
Main Methods:
- Whole-exome sequencing was performed on 87 patients from 64 families with MCPH or syndromic PM.
- Genetic variants were analyzed for pathogenicity, and clinical features were correlated with genotypes.
Main Results:
- A diagnostic yield of 53.1% was achieved, identifying 34 disease-causing variants, 15 of which were novel.
- MCPH-associated genes were found in 17.2% of families, syndromic PM in 35.9%.
- Distinct gene pathway associations (mitotic division/DNA repair for MCPH; transcription regulation/cell trafficking for syndromic PM) and clinical phenotypes (intellectual disability severity, behavioral issues, facial gestalt) were observed.
Conclusions:
- Exome sequencing is effective for diagnosing MCPH and syndromic PM, revealing significant genetic heterogeneity.
- Distinct genetic and clinical profiles differentiate MCPH from syndromic PM.
- The study identified KNTC1 as a potential candidate gene, expanding the genetic landscape of these disorders.
