Renal agenesis-related genes are associated with Herlyn-Werner-Wunderlich syndrome.

Objective: To explore the genetic causes of Herlyn-Werner-Wunderlich syndrome (HWWS) using whole-exome sequencing.

Design: Retrospective genetic study.

Setting: Academic medical center.

Patient(s): Twelve patients with HWWS.

Intervention(s): Whole-exome sequencing was performed for each patient. Sanger sequencing was used to confirm the potential causative genetic variants. In silico analysis and American College of Medical Genetics and Genomics guidelines were used to classify the pathogenicity of each variant.

Main Outcome Measure(s): Rare sequence variants associated with müllerian duct development and renal agenesis were identified and included in subsequent analyses.

Result(s): A total of 11 variants were identified in 10 of 12 patients (83.3%) and were considered to constitute a molecular genetic diagnosis of HWWS. These 11 variants were related to 9 genes: CHD1L, TRIM32, TGFBR3, WNT4, RET, FRAS1, FAT1, FOXF1, and PCSK5. All variants were heterozygous and confirmed by Sanger sequencing. The changes included one frameshift variant, one splice-site variant, and eight missense variants. All of the identified variants were absent or rare in Genome Aggregation Database East Asian populations. One of the 11 variants (9.1%) was classified as a pathogenic variant according to the American College of Medical Genetics and Genomics guidelines, and 8 of the 11 variants (72.7%) were classified as variants of uncertain significance.

Conclusion(s): To our knowledge, this is the first report of the genetic causes of HWWS. Renal agenesis-related genes, such as CHD1L, TRIM32, RET, and WNT4, may be associated with HWWS. Identification of these variants can not only help us understand the etiology of HWWS and the relationship between reproductive tract development and urinary system development, but additionally improve the level of genetic counseling for HWWS.