Clin Genet. 2020 Oct;98(4):402407. 10.1111/cge.13816. PMID: 32683677.
This short report describes two 46,XY siblings of consanguineous parents manifesting a complex syndrome consisting of multiple dysmorphic features including growth and developmental retardation, gastrointestinal disorders, musculoskeletal and cardiac anomalies, as well as ambiguous genitalia (non-palpable testes, micropenis, underdeveloped scrotum). Whole exome sequencing revealed a homozygous novel splicing variant in the COG6 gene important for glycosylation.
Although this case report provides only clinical and genetic data, it puts the findings nicely into the context of published knowledge on congenital disorders of glycosylation (CDG). Studying the reported cases in the literature, the authors recognize that so far the DSD phenotype of several CDGs was disregarded, although present in at least 13 CDGs identified by a recent review (1). Related to sex development, it is noted that FSH, LH and their receptors belong to the family of glycoprotein hormones, for which the glycans play important roles for proper dimerization, stability, secretion and signaling. However, the observed DSD phenotype in several CDGs suggests disruption of early events in sexual development that are independent of gonadotropin secretion and action. Thus, the exact targets of glycosylation in the pathogenesis of DSDs is currently unknown and this needs to be further explored, but genetic data clearly indicate but genetic data clearly indicate that pathogenic variants in CDG genes are associated with various DSD phenotypes.
With current methods, the genetic cause of about half of DSD cases can be solved. This study illustrates how powerful unbiased next generation sequencing (NGS) approaches are in discovering novel genetic causes and potential mechanisms of DSD. Whole exome sequencing has become the method of choice in routine genetic diagnostic of DSDs and is replacing candidate gene and panel analyses. I agree with the authors that variants in genes causing CDGs should be added to the list of syndromic forms of DSDs. In the same line, we learn from those CDG cases with a DSD phenotype that proper glycosylation is needed for normal human sexual development.
Reference 1. Péanne R, de Lonlay P, Foulquier F, et al. Congenital disorders of glycosylation (CDG): quo vadis? Eur J Med Genet. 2018;61(11):643–663. doi: https://doi.org/10.1016/j.ejmg.2017.10.012.