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

Area of Science:

• Genetics
• Endocrinology
• Developmental Biology

Background:

• SOX11 gene variants are known to cause Coffin-Siris syndrome.
• Coffin-Siris syndrome is characterized by developmental delay, hypogonadotropic hypogonadism, and skeletal and facial defects.

Purpose of the Study:

• To investigate the role of SOX11 variants in the development of idiopathic hypogonadotropic hypogonadism (IHH).
• To understand the contribution of SOX11 variants to GnRH deficiency in IHH.

Main Methods:

• Exome sequencing was performed on 1810 unrelated IHH probands.
• Rare SOX11 single nucleotide variants (SNVs) were identified and analyzed.
• Phenotypic data of individuals with pathogenic SOX11 SNVs were collected and evaluated.

Main Results:

• Four pathogenic SOX11 SNVs were found in 5 IHH probands.
• SOX11 protein-truncating and missense variants were significantly enriched in the IHH cohort.
• SOX11 variant carriers exhibited a spectrum of endocrine defects, including IHH, GH deficiency, and hypothyroidism, with some showing Coffin-Siris syndrome features.

Conclusions:

• Deleterious SOX11 variants are a cause of IHH and other pituitary hormone deficiencies.
• The human SOX11-associated disorder likely involves defects at both hypothalamic and pituitary levels.