Biallelic variants in RNU12 cause CDAGS syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• CDAGS Syndrome is a rare congenital disorder with diverse clinical manifestations including craniosynostosis, fontanelle abnormalities, cranial defects, clavicular hypoplasia, and anal, genitourinary, and skin anomalies.
• The genetic basis of CDAGS Syndrome has remained largely elusive, hindering a comprehensive understanding of its pathogenesis.

Purpose of the Study:

• To identify the molecular cause of CDAGS Syndrome in affected individuals.
• To elucidate the role of the identified gene in the complex phenotype of CDAGS Syndrome.

Main Methods:

• Whole exome sequencing and Sanger sequencing were employed to analyze genetic variations in five patients from four families.
• Whole transcriptome sequencing and differential alternative splicing analysis were performed on patient-derived lymphoblastoid cells.

Main Results:

• Biallelic rare variants in the RNU12 gene were identified as the underlying cause of CDAGS Syndrome.
• The identified mutations disrupt conserved nucleotides in the RNU12 gene, affecting precursor U12 snRNA structure and function.
• RNU12 is essential for minor intron splicing, and its dysfunction leads to altered gene expression and splicing patterns.

Conclusions:

• Mutations in the RNU12 gene are responsible for CDAGS Syndrome, highlighting its critical role in human development.
• The findings implicate RNU12 in the pathogenesis of craniosynostosis, anal and genitourinary malformations, and skin manifestations.
• This study provides a molecular basis for CDAGS Syndrome and opens avenues for future research and potential therapeutic strategies.