Novel neuroclinical findings of autosomal recessive primary microcephaly 15 in a consanguineous Iranian family.

Major facilitator superfamily domain-containing 2A (MFSD2A) is required for brain uptake of Docosahexaenoic acid and Lysophosphatidylcholine, both are essential for the normal neural development and function. Mutations in MFSD2A dysregulate the activity of this transporter in brain endothelial cells and can lead to microcephaly. In this study, we describe an 11-year-old male who is affected by autosomal recessive primary microcephaly 15. This patient also shows severe intellectual disability, recurrent respiratory and renal infections, low birth weight, and developmental delay. After doing clinical and neuroimaging evaluations, due to heterogeneity of neurogenetic disorders, no narrow clinical diagnosis was possible, therefore, we utilized targeted-exome sequencing to identify any causative genetic factors. This revealed a homozygous in-frame deletion (NM_001136493.1: c.241_243del; p.(Val81del)) in the MFSD2A gene as the most likely disease-susceptibility variant which was confirmed by Sanger sequencing. Neuroimaging revealed lateral ventricular asymmetry, corpus callosum hypoplasia, type B of cisterna magna, and widening of Sylvian fissures. All of these novel phenotypes are associated with autosomal recessive primary microcephaly-15 (MCPH15). According to the genotype-phenotype data, p.(Val81del) can be considered a likely pathogenic variant leading to non-lethal microcephaly. However, further cumulative data and molecular approaches are required to accurately identify genotype-phenotype correlations in MFSD2A.

Whole-exome sequencing identified a novel variant in an Iranian patient affected by pycnodysostosis.

BACKGROUND: Whole-exome sequencing (WES) has emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. In this study, we aimed to find the potential genetic cause of skeletal disease, a heterogeneous disease, revealing the obvious short stature phenotype. In an Iranian family, we used solo-WES in a suspected patient to decipher the potential genetic cause(s). METHODS: A comprehensive clinical and genotyping examination was applied to suspect the disease of the patient. The solo clinical WES was exploited, and the derived data were filtered according to the standard pipelines. In order to validate the WES finding, the region harboring the candidate variant in the CTSK gene was amplified from genomic DNA and sequenced directly by Sanger sequencing. RESULTS: Sequence analysis revealed a rare novel nonsense variant, p.(Trp320*); c.905G>A, in the CTSK gene (NM_000396.3). In silico analysis shed light on the contribution of the variant to the pathogenicity of pycnodysostosis. This variant was confirmed by Sanger sequencing and further clinical examinations of the patient confirmed the disease. CONCLUSION: The present study shows a rare variant of the CTSK gene, which inherited as autosomal recessive, in an Iranian male patient with pycnodysostosis. Taken together, the novel nonsense CTSK variant meets the criteria of being likely pathogenic according to the American College of Medical Genetics and Genomics-the Association for Molecular Pathology (ACMG-AMP) variant interpretation guidelines.