Kidney Week

Abstract: SA-PO576

Whole Exome Sequencing Identifies Causative Mutations in 16% and Novel Candidate Genes in 24% of Individuals with a Diagnosis of CAKUT

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 802 Non-Cystic Mendelian Diseases

Authors

• Connaughton, Dervla M., Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Dervla M. Connaughton,

• van der Ven, Amelie, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Amelie van der Ven,

• Ityel, Hadas, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Hadas Ityel,

• Shril, Shirlee, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shirlee Shril,

• Mann, Nina, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Nina Mann,

• Nakayama, Makiko, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Makiko Nakayama,

• Chen, Jing, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Jing Chen,

• Vivante, Asaf, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Asaf Vivante,

• Hwang, Daw-yang, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Daw-yang Hwang,

• Widmeier, Eugen, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Eugen Widmeier,

• Schulz, Julian Jakob, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Julian Jakob Schulz,

• Tasic, Velibor, University Children's Hospital, Skopje, Macedonia (the former Yugoslav Republic of)

Velibor Tasic,

• Mane, Shrikant M., Yale University, New Haven, Connecticut, United States

Shrikant M. Mane,

• Hildebrandt, Friedhelm, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Congenital anomalies of the kidney and urinary tract (CAKUT) cause 50% of chronic kidney disease in children. Several lines of evidence support the hypothesis that CAKUT has a monogenic origin: i) congenital nature, ii) monogenic multi-organ syndromes with CAKUT, iii) familial occurrence, iv) monogenic mouse models and v) the complex genetics underlying renal morphogenesis. About 40 monogenic causes of CAKUT are known so far, explaining ~17% of cases.

Methods

We applied whole exome sequencing (WES) to 135 individuals from 76 families with CAKUT. WES data were evaluated for mutations in known causes of CAKUT in humans (~40 genes), and novel candidate genes for syndromic (~200 genes) or murine CAKUT (~180 genes). In consanguineous or multiplex families, we also performed a search for novel recessive CAKUT genes (14/76) or trio analysis (24/76), respectively.

Results

In 9/76 (12%) families, a causative mutation in a known gene for isolated or syndromic CAKUT was identified that sufficiently explained the respective patients phenotype. In 3/76 (4%) of families, a mutation was identified in a gene causing a kidney disease that may represent a phenocopy of CAKUT (e.g. small kidneys). When evaluating candidate genes for human syndromic CAKUT, we detected deleterious mutations in 5/76 (7%) families with isolated CAKUT. In 1 family, mutations in a mouse candidate gene was identified. In 14/76 consanguineous and 24/76 non-consanguineous families we additionally applied a targeted search for homozygously mutated genes or trio analysis, respectively, and identified 12 potential novel candidate genes for CAKUT.

Conclusion

By WES, we detected causative mutations in 16% of cases with a diagnosis of CAKUT and identified 12 potential novel CAKUT genes. We show that syndromic and murine candidate genes are useful to identify genetic causes of isolated human CAKUT.

Funding

• Other NIH Support