Rare Biallelic CTU2 Variants in an Individual With CAKUT: Clinical Characterization and Minigene Splicing Analysis

Area of Science:

• Genetics
• Nephrology
• Developmental Biology

Background:

• Congenital anomalies of the kidney and urinary tract (CAKUT) are diverse and often lack genetic explanations.
• Biallelic CTU2 variants cause DREAM-PL syndrome, but CTU2's role in isolated CAKUT is unknown.

Purpose of the Study:

• Investigate the potential involvement of CTU2 variants in patients diagnosed with CAKUT.
• Determine the functional impact of identified CTU2 variants on splicing.

Main Methods:

• Exome sequencing in 200 CAKUT patients.
• Variant validation via Sanger sequencing and segregation analysis.
• In silico prediction and minigene splicing assays to assess functional effects.

Main Results:

• Identified compound heterozygous CTU2 variants (c.913C>T and c.1492C>G) in a CAKUT patient with bilateral hydronephrosis and chronic kidney disease.
• The c.913C>T variant was shown to alter pre-mRNA splicing by increasing exon 9 skipping.
• The c.1492C>G variant did not significantly affect exon inclusion.

Conclusions:

• Two rare CTU2 variants were found in a patient with renal-predominant CAKUT.
• In vitro evidence suggests c.913C>T partially affects splicing, warranting further investigation.
• CTU2 warrants further study in renal developmental disorders, though not yet confirmed as a sole cause of isolated CAKUT.