Abstract
The 46, XY disorder of sex development (DSD) is the main cause of birth defects; however, as it is a group of highly heterogeneous diseases, >50% of cases are not accurately diagnosed. Identification of more cases will improve understanding of the relationship between genotype and phenotype for DSD. The present study conducted a systematic analysis of the clinical characteristics of a proband with 46, XY DSD, applied genetic analysis by whole‑exome sequencing to this pedigree and performed bioinformatics analysis of the identified variant. The proband presented with a short penis, lack of testicles and partial growth hormone (GH) deficiency at 1 year old. Histopathological examination revealed there were oviduct, epididymis and fibrous vascular tissue on both sides of the abdomen. The last follow‑up at 5 years of age revealed that the patient exhibited restricted growth, a 1.5‑cm penis and lack of testicles. Notably, a novel pathogenic mitogen‑activated protein kinase kinase kinase 1 (MAP3K1) variant (c.3020A>G) was identified in the proband, resulting in a change in the 1,007th amino acid (glutamine) of the encoded protein. This variant caused the uncharged neutral glutamine to be replaced by a positively charged basic arginine. p.Gln1007 in MAP3K1 was confirmed to be conserved across various species. Pathogenicity analysis using bioinformatics tools suggested that this MAP3K1 variant may cause functional defects. In conclusion, the present study identified a novel MAP3K1 variant that was the cause of 46, XY DSD and partial GH deficiency. The present findings extend the mutation spectrum of MAP3K1 and provide novel characteristics of 46, XY DSD.