X-linked mental retardation-hypotonic facies syndrome: Exome sequencing identifies novel clinical characteristics associated with c.5182G&gt;C mutation in the <i>ATRX</i> gene

Abstract

Background: X-linked mental retardation-hypotonic facies syndrome-1 (MRXFH1), caused by a mutation in the ATRX gene, is a rare syndromic form of X-linked mental retardation (XLMR) that is mainly characterized by severe intellectual disability, dysmorphic facies, and skewed X-inactivation pattern in carrier women. Method: In this study, due to the genetic heterogeneity of the disease, we performed exome sequencing (ES) on a 15-year-old boy with primary microcephaly and intellectual disability. Also, Sanger sequencing, cosegregation analysis, and structural modeling were done to identify and verify the causative variant in the proband and other affected individuals in the family. In addition, we collected data from previously reported cases to compare with our patients' phenotypes. Results: ES revealed a previously reported missense variant in the ATRX gene (c.5182G > C, p.Ala1728Pro), segregating with the new clinical characteristic including primary microcephaly in the pedigree. This variant meets the criteria of being likely pathogenic based on the ACMG variant interpretation guideline. Conclusions: The findings of this study extend the spectrum of phenotypes associated with the identified variant and provide further details on its clinical features.