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

contextSOX11 variants cause Coffin-Siris syndrome, characterized by developmental delay, hypogonadotropic hypogonadism, and skeletal and facial defects.

objectiveTo examine the contribution of SOX11 variants to the pathogenesis of idiopathic hypogonadotropic hypogonadism (IHH), a disorder caused by hypothalamic GnRH deficiency.

settingThe Reproductive Endocrine Unit and the Pediatric Endocrinology Division, Massachusetts General Hospital. PATIENTS OR OTHER

participantsA cohort of 1810 unrelated IHH probands.

interventionsExome 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/

resultsFour 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.

conclusionDeleterious 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.