Expanding the Spectrum of Endocrine Abnormalities Associated With SOX11-related Disorders

Abstract Context SOX11 variants cause Coffin-Siris syndrome, characterized by developmental delay, hypogonadotropic hypogonadism, and skeletal and facial defects. Objective To examine the contribution of SOX11 variants to the pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency. Setting The Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital. Patients or other participants A cohort of 1810 unrelated IHH probands. Interventions Exome sequencing data from the entire cohort were examined for SOX11 rare single nucleotide variants (SNVs) (minor allele frequency in the gnomAD database <0.1%). Rare SOX11 variant association testing was performed between the IHH and gnomAD population. Phenotyping of individuals harboring pathogenic/likely pathogenic SNVs (determined by the American College of Medical Genetics criteria) was performed. Main Outcomes/Results Four pathogenic SOX11 SNVs were identified in 5 IHH probands. The IHH cohort was enriched for SOX11 protein truncating SNVs (frameshift/nonsense) across the entire protein (2 SNVs in 3 IHH cases [p.S303X (de novo); p.S345Afs*13]; P = .0004981) and for SOX11 missense SNVs within the SOX11 high-mobility group domain (2 SNVs in 2 IHH cases p.G84D [de novo]; p.P114S; P = .00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, GH deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional hypogonadotropic hypogonadism (p.R100Q). Coffin-Siris syndrome-associated features were present in 4/5 probands. Conclusion Deleterious SOX11 variants cause IHH and other pituitary hormone deficiencies, suggesting that the human SOX11-associated disorder may stem from both hypothalamic and pituitary level defects.