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.

Keywords: SOX11; genetics; hypogonadotropic hypogonadism; hypothalamus; pituitary.

Figure 1.

Pedigrees with pathogenic SOX11 single nucleotide variants (SNVs) identified in this study. Probands are identified by arrows. Amino acid changes are named according to RefSeq ID: NP_003099.1. Abbreviations: CSS, Coffin-Siris syndrome; FHH, functional hypogonadotropic hypogonadism; KS, Kallmann syndrome; M, mutant allele; nIHH, normosmic idiopathic hypogonadotropic hypogonadism; WT, wild-type allele.

Figure 2.

(A) SOX11 protein schematic showing the localization of 16 SOX11 variants identified in IHH and FHH patients. The variants labeled above the schematic are defined as pathogenic according to the ACMG guidelines, whereas the variants below are considered either benign or of uncertain significance. The R100Q variant identified in the FHH patient is also shown. Amino acid changes are named according to RefSeq ID: NP_003099.1. (B) Multiple protein sequence alignment showing evolutionary conservation of the 3 pathogenic missense variants. All 3 positions localized to the HMG box domain are highly constrained. Abbreviations: HMG, high-mobility group; TAD, transactivating domain.

Figure 3.

HH-associated SOX11 HMG domain visualized on a 3-dimensional homology model. The mutated residues are depicted using homology modeling based on the structure of the human SOX9 HMG domain (PDB ID 4s2q).