Whole exome sequencing identified a homozygous novel variant in DOP1A gene in the Pakistan family with neurodevelopmental disabilities: case report and literature review

• Published in: Frontiers in genetics 2024-05, Vol.15, p.1351710
• Main Authors: Zhang, Wei, Tariq, Muhammad, Roy, Bhaskar, Shen, Juan, Khan, Ayaz, Altaf Malik, Naveed, He, Sijie, Baig, Shahid Mahmood, Fang, Xiaodong, Zhang, Jianguo
• Format: Article
• Language: English
• Subjects: DOP1A; Genetics; Mon2; myelin-associate glycoprotein (MAG); myelination; neurodevelopmental disorders (NDDs); proteolipid protein (PLP)
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2024.1351710

Hereditary neurodevelopmental disorders (NDDs) are prevalent in poorly prognostic pediatric diseases, but the pathogenesis of NDDs is still unclear. Irregular myelination could be one of the possible causes of NDDs. Here, whole exome sequencing was carried out for a consanguineous Pakistani family with NDDs to identify disease-associated variants. The co-segregation of candidate variants in the family was validated using Sanger sequencing. The potential impact of the gene on NDDs has been supported by conservation analysis, protein prediction, and expression analysis. A novel homozygous variant was identified. It was concluded that the missense variant might affect the protein-protein binding sites of the critical MEC interaction region of DOP1A, and DOP1A-MON2 may cause stability deficits in Golgi-endosome protein traffic. Proteolipid protein (PLP) and myelin-associate glycoprotein (MAG) could be targets of the DOP1A-MON2 Golgi-endosome traffic complex, especially during the fetal stage and the early developmental stages. This further supports the perspective that disorganized myelinogenesis due to congenital deficiency might cause neurodevelopmental disorders (NDDs). Our case study revealed the potential pathway of myelinogenesis-relevant NDDs and identified as a potential NDDs-relevant gene in humans.