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Kidney Week

Abstract: TH-PO704

COL4A1 Mutations as a Potential Novel Cause of Autosomal-Dominant CAKUT in Humans

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Kitzler, Thomas, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kolvenbach, Caroline M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Schneider, Ronen, Boston Children's Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Mann, Nina, Boston Children's Hospital, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease <30 years of age. While the genetic locus containing COL4A1 (13q33-34) has been implicated in vesicoureteral reflux (VUR), the role of COL4A1 in isolated kidney disease is unclear (Vats JASN 17:1158, 2006). We hypothesized that mutations in COL4A1 can cause abnormal kidney development in humans.

Methods

We performed whole exome sequencing in a cohort of 638 families (258 families with nephronophthisis (NPHP) and 380 families with CAKUT). Genetic variants were analyzed assessing evolutionary conservation, in-silico prediction programs, and minor allele frequency in public databases (gnomAD, EVS, 1000 Genomes), as previously described (Braun Nat Genet 49:1529, 2017).

Results

We identified eight different heterozygous mutations in COL4A1 in eight unrelated families with CAKUT, while no COL4A1 mutations were present in the NPHP negative control cohort. All eight individuals had heterozygous only missense variants in COL4A1 (D928H, G1392S, G1450S L1235R, M838V, P603S, P816L, P1224L) with an isolated CAKUT phenotype. Affected individuals exhibited a spectrum of CAKUT phenotypes ranging from renal agenesis, small echogenic dysplastic kidneys, multicystic dysplastic kidney, left ectopic dysplastic kidney, hydronephrosis, to VUR. VUR was the predominant phenotype (5/8 families). Three patients had extra-renal features (facial dysmorphism, low set ears, hypotelorism, hearing loss, and uterus unicornis). COL4A1 demonstrates extreme loss-of-function intolerance (pLI = 1), supporting autosomal dominant inheritance.

Conclusion

We identified heterozygous COL4A1 mutations as a potential novel autosomal dominant cause of CAKUT. The observation that some patients exhibit an extra-renal phenotype, while others have isolated CAKUT, suggests the possibility of allelism.

Funding

  • NIDDK Support