Clinical and genetic findings in an Iraqi family with TMEM67-associated Joubert syndrome

Abstract

Joubert syndrome is a rare, genetically complex disorder that significantly affects brain development, characterized by hallmark features such as hypotonia, developmental and motor delays, and the distinctive molar tooth sign on brain MRI. The disorder frequently arises from mutations in genes essential for ciliary function, crucial for cellular signaling and development across multiple organ systems. TMEM67, one of these genes, is particularly associated with cases involving multi-organ dysfunction, including kidney and liver abnormalities. We report a novel homozygous mutation in TMEM67 (c.797A>T; p.Asp266Val) in a 7-year-old male from a consanguineous Iraqi family, who presented with classic neurological symptoms of Joubert syndrome and mild hepatic dysfunction. The mutation, located in exon 8 (NM_153704.6), substitutes aspartic acid with valine, likely disrupting protein structural integrity and function through the loss of polar charge. Using exome and Sanger sequencing, we confirmed this pathogenic variant, emphasizing the necessity of comprehensive genetic analysis for accurate diagnosis and management, especially in populations with high consanguinity rates. Our findings expand the mutational spectrum of TMEM67 and highlight potential mutation hotspots related to severe multi-organ involvement. This study enriches the TMEM67 variant database and stresses the importance of genetic counseling for guiding patient care and reproductive decisions.