<i>SOX2</i> nonsense mutation in a patient clinically diagnosed with non-syndromic hypogonadotropic hypogonadism

Abstract

Hypogonadotropic hypogonadism (HH) is a genetically heterogeneous condition that occurs either as an isolated disorder or as a component of congenital malformation syndromes. SOX2 is a causative gene of syndromic HH characterized by anophthalmia, microphthalmia, or coloboma and other neurological defects such as epilepsy. To date, the causal relationship between SOX2 abnormalities and non-syndromic HH remains speculative. Here, we identified a nonsense mutation of SOX2 in a male patient clinically diagnosed with non-syndromic HH. The patient had epilepsy but no additional clinical features. Ophthalmological examination revealed no abnormalities except for decreased thickness of the retinal nerve fiber layer. Audiometry showed mild sensorineural hearing impairment of both ears. Hormonal evaluation suggested isolated gonadotropin deficiency. Next-generation sequencing-based mutation screening of 13 major causative genes for HH identified a p.Lys35 mutation in SOX2 and excluded pathogenic mutations in other tested genes. The p.Lys35 mutation appeared to encode a non-functioning SOX2 protein that lacks 283 of 317 amino acids. The SOX2 mutation was absent in the maternal DNA sample, while a paternal sample was unavailable for sequence analysis. These results expand the clinical consequences of SOX2 haploinsufficiency to include non-syndromic HH. Systematic mutation screening using a next-generation sequencer and detailed evaluation of nonspecific ocular/neurological features may help identify SOX2 mutation-positive individuals among HH patients.

Extension of the mutational and clinical spectrum of SOX2 related disorders: Description of six new cases and a novel association with suprasellar teratoma

“…With the increased utilization of NGS technologies in the clinic, more cases are being uncovered, including those that expand the known phenotypic spectrum. Interestingly, SOX2 pathogenic variants have been reported in a few subjects with normal ocular development, including c.70del20 (p.[Asn24Argfs*65]) (Zenteno et al, ; Errichiello et al, 2018), c.837delC (p.Gly280Alafs*91) (Stark, Storen, Bennetts, Savarirayan, & Jamieson, ), c.224 T > A (p.Leu75Gln) (Sato et al, ), c.103A > T (p.Lys35*) (Shima et al, ), and a 1.57 Mb deletion involving SOX2 (Dennert et al, ). No obvious genotype–phenotype correlation appears to exist in this subgroup of cases.…”

“…Remarkably, SOX2 variants have been identified in individuals suffering from non‐ocular congenital anomalies, including isolated hypogonadotropic hypogonadism, esophageal atresia, or intellectual disability (Sato et al, ; Zenteno, Perez‐Cano, & Aguinaga, ; Shima et al, ; Dennert et al, ; Errichielo et al, 2018), highlighting the extensive phenotypic variability resulting from variants in SOX2. Thus, the description of novel pathogenic variants in this gene and their resulting phenotypes is warranted as it allows a more complete characterization of the spectrum of human developmental defects arising from SOX2 variation.…”

SOX2 heterozygous mutation causes multiple extra-ocular phenotypes in boys

“…Heterozygous mutations in the SOX2 gene could lead to syndromic HH with A/M/coloboma [4,5,9]. Since 2003, only 6 cases (4.9%) of patients with non-syndromic HH (except for absense of puberty, some patients also show micropenis and/or cryptorchidism) have been reported [8,11,14,30,[38][39], while micropenis and cyptorchidism are the main clues of HH during childhood. The 3 patients in our study are currently young and need further follow-up.…”

“…The single exon gene encodes a protein of 317 residues, which includes an N-terminal domain, a DNA-binding HMG (high-motility group) domain and a transcriptional activation domain in C-terminal [7]. At present, more than 100 cases of ophthalmology patients with A / M or other major ocular anomalies have been reported to have SOX2 mutations, mainly truncating variants caused by nonsense or frameshift [8][9][10][11][12]. SOX2 plays a pivotal role in the development of hypothalamopituitary by transactivation of mutiple genes including HESX1, and its mutations can cause hypophysial hypoplasia, reduce gonadotropin secretion, thus causing genital tract abnormalities or no puberty [2,13].…”

“…SOX2 plays a pivotal role in the development of hypothalamopituitary by transactivation of mutiple genes including HESX1, and its mutations can cause hypophysial hypoplasia, reduce gonadotropin secretion, thus causing genital tract abnormalities or no puberty [2,13]. Several studies found that SOX2 heterozygous mutations cause typical signs of complete hypogonadism without major ocular malformations in men or women, say, isolated hypogonatropic hypogonadism (HH), but no another HH pathogenic gene was identified [10][11]14]. And no such Chinese patients were reported as well.…”