Joubert syndrome caused by a TMEM67 mutation: Genotype-phenotype analysis

Abstract

Joubert syndrome (JS), a rare neurodevelopmental disorder, is characterized by a unique midbrain-hindbrain malformation known as the molar tooth sign, a distinctive radiological feature. Among the myriad manifestations associated with JS, the most prevalent features encompass hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing abnormalities. To date, 29 genes have been identified as contributors to the development of JS. This study aimed to pinpoint a pathogenic variant in JS within an Iranian consanguineous pedigree. We employed whole-exome sequencing (WES) to pinpoint a potential pathogenic variant likely responsible for the condition in an 8-year-old male patient. The WES analysis successfully revealed a novel homozygous missense mutation (c.725A>T; p.Asn242Ile) within exon 8 (NM_153704.6) of the TMEM67 gene. Subsequent validation through Sanger sequencing confirmed the presence of the chr8-93780603A>T mutation. This study elucidated JS within an Iranian family, uncovering a new TMEM67 gene mutation through comprehensive genetic analysis. The identification of this mutation enhances our understanding of the genetic landscape of JS, contributing valuable insights for both clinical diagnosis and future research endeavors.