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Abstract: TH-PO665

Rare Deleterious Collagen IV Gene Variants Are Overrepresented in “No Mutation Detected” ADPKD Patients

Session Information

Category: Genetic Diseases of the Kidney

  • 1001 Genetic Diseases of the Kidney: Cystic


  • Gulati, Ashima, Yale University, New Haven, Connecticut, United States
  • Choi, Jungmin, Yale University , New Haven, Connecticut, United States
  • Somlo, Stefan, Yale University, New Haven, Connecticut, United States

Genetic investigation of autosomal dominant polycystic kidney disease (ADPKD) cohorts yields the underlying PKD1 (77%) or PKD2 mutation (15% cases); 8% cases have no mutation detected (NMD) in these genes. This NMD group may include ADPKD phenocopies. Type IV collagen, an integral component of the basement membrane exists mainly as α1α1α2 and α3α4α5 heterotrimers in the kidney. Mutations in genes encoding these α-chain isoforms are linked to Alport syndrome (COL4A3, COL4A4, COL4A5), Thin GBM disease (COL4A3, COL4A4) and HANAC (hereditary angiopathy, nephropathy, aneurysms, muscle cramps) (COL4A1). Bilateral kidney cysts are reported with heterozygous COL4A1 mutations as part of HANAC syndrome and also sporadically in few patients with thin GBM disease.


A clinically and radiologically defined ADPKD cohort (N=178) constituting patients with PKD1 or PKD2 mutation (N=161) and those with NMD (N=17) in PKD1, PKD2 or other genes known to associate with polycystic kidneys (GANAB, DNAJB11 or Polycystic Liver Disease genes) was investigated using whole exome sequencing for rare (minor allele frequency <5x10-5) variants meeting deleteriousness criteria using bioinformatics scores.


Analysis of NMD patients (N=17) identified pathogenic heterozygous type IV collagen variants in four patients. These included HANAC causing COL4A1 variants in 3 patients, of which 2 had missense variants each and one patient was compound heterozygous for a COL4A1 truncating variant and a COL4A3 missense variant. One patient had a splice site COL4A4 variant that we confirmed to cause complete skipping of exon 28 by a minigene splice assay. Collagen IV variants of similar deleteriousness assessed in 161 patients with a PKD1 or PKD2 mutation revealed a significantly lower burden as compared to NMD patients (COL4A1; p-value 0.009); (COL4A3 and COL4A4; p-value 0.029). Clinical and imaging review of NMD patients with collagen IV variants showed fewer or atypical appearing cysts.


Rare deleterious mutations in COL4A1, COL4A3, COL4A4 are overrepresented in the ‘no mutation detected’ ADPKD cohort. Characterization of predicted deleteriousness of type IV collagen variants using bioinformatics scoring and splice assay is useful. The causation link, if any, between the type IV collagen genes and cystic kidneys is however elusive.


  • NIDDK Support