Kidney Week

Abstract: PO1643

In the Presence of Genetic Heterogeneity of CAKUT, Whole-Exome Sequencing Establishes a Molecular Genetic Diagnosis in 14% of Cases

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - 2
  October 22, 2020 | Location: On-Demand
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

• Seltzsam, Steve, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Steve Seltzsam,

• Wang, Chunyan, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Chunyan Wang,

• Zheng, Bixia, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Bixia Zheng,

• Wu, Chen-Han Wilfred, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Chen-Han Wilfred Wu,

• Schneider, Sophia, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Sophia Schneider,

• Schierbaum, Luca M., Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Luca M. Schierbaum,

• Connaughton, Dervla M., Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Dervla M. Connaughton,

• Van der ven, Amelie, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Amelie Van der ven,

• Mann, Nina, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Nina Mann,

• Nakayama, Makiko, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Makiko Nakayama,

• Dai, Rufeng, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Rufeng Dai,

• Kause, Franziska, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Franziska Kause,

• Kolvenbach, Caroline M., Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Caroline M. Kolvenbach,

• Mane, Shrikant M., Department of Human Genetics, Yale University School of Medicine, New Haven, Connecticut, United States

Shrikant M. Mane,

• Shril, Shirlee, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Shirlee Shril,

• Hildebrandt, Friedhelm, Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States

Friedhelm Hildebrandt,

Background

Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease in children and young adults. More than 44 monogenic causes of CAKUT have been discovered so far (NDT 35:390, 2020). The high number of unsolved consanguineous families with CAKUT strongly suggests the existence of additional monogenic causes of CAKUT.

Methods

We conducted whole exome sequencing (WES) and homozygosity mapping in an international cohort of patients with CAKUT from 211 unrelated families. We evaluated WES data for mutations in the 44 known genes that cause isolated CAKUT in humans and the 179 genes that cause syndromic CAKUT in humans. We then evaluated unsolved cases for potential novel genetic causes of CAKUT using our established criteria for variant identification (JASN 29:2348, 2018).

Results

In 30 of 211 (14%) families, we detected mutations in one of the 44 genes for isolated CAKUT or in one of the 179 syndromic CAKUT genes. In particular syndromic cases, reverse phenotyping was helpful to increase certainty of the deleteriousness of a genetic variant. In the remainder, we performed a targeted analysis for novel candidate genes. In 40 families of this subset, we identified likely deleterious mutations in 36 genes not previously reported to cause CAKUT.

Conclusion

In a large, international cohort we detected causative mutations in 14% of families with a diagnosis of CAKUT. We show that when combined with homozygosity mapping and segregation analysis, WES is useful in identifying potential candidate genes in consanguineous families or families with multiple affecteds.