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

Abstract Context SOX11 variants cause Coffin-Siris Syndrome (CSS), characterized by developmental delay, hypogonadotropic hypogonadism (HH), 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 ACMG 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 0.0004981) and for SOX11 missense SNVs within the SOX11-high-mobility group (HMG) domain (2 SNVs in 2 IHH cases p.G84D[de-novo]; p.P114S; p=0.00313922). The phenotypic spectrum of SOX11 variant carriers revealed additional endocrine defects including anosmic and normosmic forms of IHH, growth-hormone deficiency, pituitary and hypothalamic structural defects, and hypothyroidism. A pathogenic SOX11 SNV was also identified in a patient with functional HH (FHH, p.R100Q). CSS-associated features were present in 4/5 probands. Conclusions 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.