Disorders of sex development associated with MPI and RSPH1 variants expand the phenotypic spectrum of CDG and PCD in...

Human sex development is a highly regulated process guiding undifferentiated gonads toward a testicular or ovarian fate. Disruptions in this pathway result in disorders of sexual development (DSD), characterized by atypical chromosomal, gonadal, or anatomical sex. These conditions usually appear as ambiguous genitalia at birth or as atypical pubertal development during adolescence. Different etiologic, phenotypic, and genotypic factors can cause DSD. Advances in next-generation sequencing (NGS) have significantly accelerated the identification of genetic variants through targeted panels, including both known genes involved in sex determination and differentiation, as well as newly discovered genes linked to DSD.

In this study, whole exome sequencing (WES) was performed on a Moroccan patient, born to non-consanguineous parents, who presented with severe hypospadias, micropenis, and cryptorchidism, and exhibited overlapping phenotypic features consistent with congenital disorder of glycosylation (CDG) and primary ciliary dyskinesia (PCD). After variant annotation and prioritization, two heterozygous variants in the MPI (c.305 C > T; p. Ser102Leu) and RSPH1 (c.471 C > G; p. His157Gln) genes were identified and confirmed by Sanger sequencing in family members. Their pathogenic effects on protein structures and functions were subsequently anticipated using bioinformatic tools and molecular dynamics (MD) simulations.

To our knowledge, this is the first report of these specific variants in the context of DSD, shedding light on a unique genotype-phenotype profile associated with the patient's complex clinical presentation. The high genetic variability underlying these disorders has made molecular diagnosis challenging. Yet, genomic approaches could expand our understanding of DSD landscape and improve diagnosis, personalized interventions, and patient management.