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Abstract: FR-PO781

Phenotype Expansion of Heterozygous FOXC1 Mutations Towards Involvement of CAKUT

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Wu, Chen-Han Wilfred, Boston Children Hospital, Boston, Massachusetts, United States
  • Mann, Nina, Boston Children Hospital, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Boston Children Hospital, Boston, Massachusetts, United States
  • Nakayama, Makiko, Boston Children Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children Hospital, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children Hospital, Boston, Massachusetts, United States
Background


Heterozygous FOXC1 mutations have been identified as the cause of Axenfeld-Rieger syndrome type 3 and anterior segment dysgenesis 3. Patients present with variable eye malformations. Syndromic cases may present with abnormalities in brain, heart, blood vessels, and hearing loss. Congenital anomalies of the kidney and urinary tract (CAKUT) have not been associated with mutations in FOXC1.

Methods

In order to identify novel monogenic causes of CAKUT we performed whole exome sequencing (WES) in 514 families with CAKUT.

Results

By WES analyses, we discovered 7 FOXC1 heterozygous mutations in 8 CAKUT families. Five of the families have isolated CAKUT, while the other 3 families have syndromic CAKUT with anomalies in eyes, blood vessels, brain, bones, or facial dysmophologies. CAKUT phenotypes include renal agenesis, renal dysplasia, multicystic dysplastic kidney, ureteropelvic junction obstruction, hydronephrosis, vesicoureteral reflux, and posterior urethral valve. None of the 7 mutations were reported in patients with Axenfeld-Rieger syndrome or anterior segment dysgenesis before. Two of the mutations are absent, and the others are present in <5 individuals as heterozygote of 125,000 healthy controls in the gnomAD database. We thereby discovered CAKUT as a new phenotype of heterozygous FOXC1 mutation. Interestingly, mouse models for FOXC1 (Green, 1970; Kume et al., 1998; Kume et al., 2000; Motojima et al., 2016) show severe CAKUT with extra-renal malformations. The mode of inheritance is autosomal dominant with incomplete penetrance and variable expressivity.

To evaluate whether the presence of CAKUT in heterozygous FOXC1 mutation is due to allelism, we conducted genotype-phenotype correlations. There are 40 truncating and 34 missense mutations known in Axenfeld-Rieger syndrome or anterior segment dysgenesis. All 34 missense mutations are in the forkhead domain. In contrast, in the 8 CAKUT families, we did not find any truncating mutations and only 1 out of 4 missense mutation is in the forkhead domain.

Conclusion

We propose a phenotype expansion of FOXC1 to include CAKUT, potentially explained by allelism.

Funding

  • NIDDK Support