Objective: To investigate a genetic cause of neonatal testicular torsion in 2 siblings and paternal cryptorchidism in a Caucasian family without history of consanguinity, we performed whole exome sequencing. Patients and Methods: Targeted exon/whole-exome sequencing was performed in 2 siblings with testicular torsion. Potentially pathogenic variants passing filter criteria were validated with Sanger sequencing of parents to confirm familial segregation. Additionally, immunofluorescence staining for Raf-1, pERK (downstream from Raf-1) and c-Kit was performed on a testicular biopsy on the preserved testicle from the proband brother and compared with testicular biopsies from fertile men. Results: A potentially pathogenic variant was identified in the RAF1 gene (serine/threonine-protein kinase) in exon 7 of chromosome 3: 12645786 G > C; both brothers and father were heterozygous for the variant, while the mother was negative for this mutation. This mutation in exon 7 (chr3:) of RAF1 is predicted to be damaging as a highly conserved splicing site is disrupted. The mutation is not found in the single nucleotide polymorphism database, the 1000 Genomes Project, ExACT, or esp6500. Immunofluorescence of the testis biopsy from one of the brothers demonstrated markedly decreased expression of Raf-1 as well as pERK but similar expression of c-kit when compared with fertile controls. Conclusion: We identified a novel nonsynonymous mutation in RAF1 in n Caucasian family with testicular torsion and cryptorchidism. We present the first human evidence that the RAF/MEK/ERK pathway is associated with testicular descent.
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