Prenatal-onset TMEM67-related Joubert syndrome in two Chinese siblings: a case report

Joubert syndrome (JS) is an infrequent congenital neurodevelopmental ciliopathy characterized by the distinctive “Molar Tooth Sign” (MTS) on magnetic resonance imaging (MRI) of the brain, reflecting cerebellar vermis hypoplasia/aplasia, thickened and horizontally oriented superior cerebellar peduncles, and a deep interpeduncular fossa. TMEM67 is one of the most common JS-associated genes, with phenotypic severity ranging from prenatal lethal to juvenile-onset forms. However no previous study has reported detailed prenatal ultrasound findings in two siblings with confirmed or highly probable TMEM67 mutations in Northwest China; and our cases illustrated the severe, early-onset end of this spectrum. We report a Chinese family with two consecutive pregnancies affected by prenatal-onset TMEM67 -related JS. Trio whole-exome sequencing (Trio-WES) revealed that the proband carried compound heterozygous variants in the TMEM67 gene: a maternally inherited frameshift mutation (c.1353delA (p.Glu452Lysfs*4)), and a paternally inherited rare splice-site variant (c.576 + 4A > C), which confirmed the molecular diagnosis of JS. The brother exhibited prenatal ultrasound findings virtually identical to those of the proband, and a postnatal brain MRI performed revealed the pathognomonic MTS, thereby confirming the clinical diagnosis of JS. Confirmatory genetic testing in the brother was not pursued due to financial constraints, a transparent limitation reflecting real-world barriers to genomic medicine. This is the first report of TMEM67 -related JS from Northwest China, and this compound heterozygous TMEM67 variants expands the mutational spectrum. The striking consistency of prenatal findings underscores the importance of recognizing fourth ventricle dilation, widened cerebellar medullary cistern, and vermian hypoplasia in prenatal screening. These findings have immediate implications for prenatal diagnosis and genetic counseling.