The latest medical research on Clinical Genetics

TRAPP complexes are crucial components for intracellular transport and cellular organization. Their role in vesicle trafficking, particularly through their involvement in the secretory pathway, make them more important in neurodevelopmental mechanisms. This study aims to identify a novel genetic variant, associated with developmental delay and intellectual disability by analyzing a consanguineous Iranian family.

Here, we performed whole-exome sequencing on an Iranian family, originating from a small population. The patient presented with severe developmental delay, microcephaly, and behavioral abnormalities. Through our analysis, we discovered a new biallelic variant on a previously introduced gene: TRAPPC10 (NM_003274.5): c.3222 C > A; p.(Cys1074Ter) that is a potential cause for these specific clinical characteristics.

Previous functional analysis suggest that the mutation causes premature termination of protein translation, likely leading to nonsense-mediated decay because of biallelic loss of functional TRAPPC10 protein which leads to severe developmental delay, microcephaly, and behavioral abnormalities such as aggression and autistic traits.

The aim of this research is to discover a novel variant in the TRAPPC10 gene that is responsible for a particular neurodevelopmental condition, dominantly characterized by developmental delay, intellectual disability, and microcephaly. These findings advance the comprehension of TRAPP-related diseases and emphasize the need for further exploration into the impact of TRAPPC10 on the development of the nervous system.

Retinitis pigmentosa (RP) is a hereditary retinal disorder that gradually leads to vision loss due to photoreceptor cell degeneration. This study aims to investigate the clinical features and genetic underpinnings of RP within a large Iranian family. Our focus centered on mutations in the NR2E3 gene, which plays a critical role in the development and maintenance of the retina.

Twenty-five family members showed symptoms of RP, and fourteen of them underwent clinical examinations conducted by geneticists and ophthalmologists. The DNA samples of five individuals diagnosed with RP from the family were subjected to whole-exome sequencing (WES) as part of the study. The candidate variant identified through WES was subsequently confirmed using bidirectional sequencing in additional family members. Additionally, in silico analysis, including molecular modeling, protein-protein docking, and molecular dynamics simulation (MD), was employed to assess potential pathogenic effects associated with the candidate variants.

Ophthalmic examination revealed night blindness, which is a common symptom among affected individuals. Genetic analysis identified a homozygous missense variant (c.934G>A/p.R311Q) in NR2E3 exon 6, which co-segregates with other affected family members. Furthermore, molecular docking analysis indicated potential disruption in the binding affinity between NR2E3 and NR1D1 proteins. In-depth, molecular dynamics analysis, considering parameters such as RMSD, RMSF, and hydrogen bonding, revealed notable differences between normal and mutant protein complexes.

Exploring the molecular interaction between NR2E3 and NR1D1 provides new insights into the pathogenic mechanism of the p.R311Q mutation in RP.