RESUMEN
Intellectual disability (ID) is a highly heterogeneous disorder, affecting 1-3% of the world's population, which is associated with a significant disorder in cognitive development, adaptive functioning and behavioural problems in human life. In this study, due to the genetic heterogeneity of the disease, the whole-exome sequencing (WES) was performed on a 13-year-old boy suffering from microcephaly. In addition, Sanger sequencing, cosegregation analysis, and structural modelling were performed to identify and verify the causative variant in the proband and obligate carriers in the family. WES revealed a novel, homozygote 10-bp deletion in the donor splice site of 2nd exon of METTL5 gene (NM_014168:c.223_224?8del), which was found segregating with the phenotype in the pedigree. This variant meets the criteria of being pathogenic according to the American College of Medical Genetics (ACMG) variant interpretation guideline. Up to now, four pathogenic homozygous variants of the METTL5 gene have been reported that are associated with ID. A comparison of the clinical characteristics of our patient with previously reported cases revealed variability in the disease severity and some clinical presentations, including overall growth, dysmorphic facial features and behavioural psychiatric manifestations. The clinical findings of the case reported in this study extend the spectrum of genetic variations and phenotypes associated with ID and provide a better insight of the disease pathogenesis.
Asunto(s)
Discapacidad Intelectual , Microcefalia , Masculino , Humanos , Adolescente , Discapacidad Intelectual/genética , Irán , Microcefalia/genética , Cognición , ExonesRESUMEN
PURPOSE: Wolfram syndrome (WS) is a rare genetic disorder described by a pattern of clinical manifestations such as diabetes mellitus, diabetes insipidus, optic nerve atrophy, sensorineural hearing loss, urinary tract abnormalities, and psychiatric disorders. WFS1 and WFS2 loci are the main genetic loci associated with this disorder. METHODS: In the current study, we investigated associations between these loci and WS via STR markers and homozygosity mapping in 13 Iranian families with WS. All families were linked to WFS1 locus. RESULTS: Mutation analysis revealed four novel mutations (Q215X, E89X, S168Del, and E391Sfs*51) in the assessed families. Bioinformatics tools confirmed the pathogenicity of the novel mutations. Other identified mutations were previously reported in other populations for their pathogenicity. CONCLUSIONS: The current study adds to the mutation repository of WS and shows a panel of mutations in Iranian population. Such panel would facilitate genetic counseling and prenatal diagnosis in families with WS cases.