Integrating clinical and genetic approaches in the diagnosis of 46,XY disorders of sex development

Abstract

46,XY differences and/or disorders of sex development (DSD) are clinically and genetically heterogeneous conditions. Although complete androgen insensitivity syndrome has a strong genotype–phenotype correlation, the other types of 46,XY DSD are less well defined, and thus, the precise diagnosis is challenging. This study focused on comparing the relationship between clinical assessment and genetic findings in a cohort of well-phenotyped patients with 46,XY DSD. The study was an analysis of clinical investigations followed by genetic testing performed on 35 patients presenting to a single center. The clinical assessment included external masculinization score (EMS), endocrine profiling and radiological evaluation. Array-comparative genomic hybridization (array-CGH) and sequencing of DSD-related genes were performed. Using an integrated approach, reaching the definitive diagnosis was possible in 12 children. The correlation between clinical and genetic findings was higher in patients with a more severe phenotype (median EMS 2.5 vs 6; P = 0.04). However, in 13 children, at least one variant of uncertain significance was identified, and most times this variant did not correspond to the original clinical diagnosis. In three patients, the genetic studies guided further clinical assessment which resulted in a reclassification of initial clinical diagnosis. Furthermore, we identified eight patients harboring variants in more than one DSD genes, which was not seen in controls (2.5%; P = 0.0003). In summary, taking into account potential challenges in reaching the definitive diagnosis in 46,XY DSD, only integrated approach seems to be the best routine practice.

Oligogenic Origin of Differences of Sex Development in Humans

“…In 46,XY patients with hypospadias, an oligogenic origin was also suggested by several HTS studies [4,5,[9][10][11][12]14] (Table 1).…”

“…Oligogenic DSD origin has been revealed either as a result of HTS directly or in a second approach, when the first candidate gene detected seemed not sufficient to explain the phenotype. Several recent studies demonstrate that many patients carry a gene variant likely responsible for the phenotype together with other variants in known or new candidate genes for DSD [4][5][6][7][8][9][10][11][12][13][14].…”

“…The patient carrying an additional ZFPM2 variant presented a more severe phenotype than another patient with the same NR5A1 variant (p.Arg84His) only; the heterozygous SRD5A2 variant (p.Arg227Gln) has been described in numerous patients with biallelic SRD5A2 mutations, but also as a monoallelic finding in patients with micropenis and/or hypospadias [9] (Table 1). Kolesinska et al [10] analyzed 37 DSD candidate genes and 21 CHH genes in 35 46,XY DSD patients; eight (23%) were found to carry gene variations in more than one candidate gene. To evaluate whether the DSD cohort was statistically enriched for oligogenicity, they compared the results to exome sequencing data from 247 male participants in the 'Cohorte Lausannoise' CoLaus control population.…”

“…Oligogenic disease has been proposed. In fact, multiple genetic hits, which might not be deleterious by themselves, have been found in individuals with DSD [4][5][6][7][8][9][10][11][12][13][14].…”

Performance of mutation pathogenicity prediction tools on missense variants associated with 46,XY differences of sex development

“…However, distinguishing rare disease-causing SNVs from rare polymorphisms remains challenging. Functional studies for disease association variants are often used, but are laborious and time-consuming ( 4 , 5 ).…”