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

Abstract

Funding informationAsociacion Para Evitar la Ceguera en Mexico; Roberts Collaborative SOX2 is a transcription factor that is essential for maintenance of pluripotency and has several conserved roles in early embryonic development. Heterozygous loss-of-function variants in SOX2 are identified in approximately 40% of all cases of bilateral anophthalmia/micropthalmia (A/M). Increasingly SOX2 mutation-positive patients without major eye findings, but with a range of other developmental disorders including autism, mild to moderate intellectual disability with or without structural brain changes, esophageal atresia, urogenital anomalies, and endocrinopathy are being reported, suggesting that the clinical phenotype associated with SOX2 loss is much broader than previously appreciated. In this report we describe six new cases, four of which carry novel pathogenic SOX2 variants. Four cases presented with bilateral anophthalmia in addition to extraocular involvement. Another individual presented with only unilateral anophthalmia. One individual did not have any eye findings but presented with a suprasellar teratoma in infancy and was found to have the recurrent c.70del20 mutation in SOX2 (c.70_89del, p.Asn24Argfs*65). This is this first time this tumor type has been reported in the context of a de novo SOX2 mutation. Notably, individuals with hypothalamic hamartomas and slow-growing hypothalamo-pituitary tumors have been reported previously, but it is still unclear how SOX2 loss contributes to their formation.

Review of 37 patients with SOX2 pathogenic variants collected by the Anophthalmia/Microphthalmia Clinical Registry and DNA research study

“…While many of the first cases in the literature with normal eyes and SOX2 variants were identified because other family members were found to have pathogenic variants (Chassaing et al, 2007; Mihelec et al, 2009; Stark et al, 2011; Zenteno et al, 2006), several were the first in their families, presenting with overlapping syndromic features including brain anomalies, hypogonadotropic hypogonadism (HH), developmental delay/intellectual disability (ID), seizures, or genital anomalies (Blackburn et al, 2018; Dennert et al, 2017; Errichiello et al, 2018; Kelberman et al, 2006; Pilz et al, 2019; Shima et al, 2017; Takagi et al, 2013). Some of these patients, on further examination, had slight ocular anomalies, such as narrowed palpebral fissure (Zenteno et al, 2006), mild retinal anomalies (Errichiello et al, 2018; Mihelec et al, 2009; Pilz et al, 2019; Shima et al, 2017; Takagi et al, 2013), subtle anterior segment anomalies (Dennert et al, 2017, Mihelec et al, 2009), ocular motility disorders (Errichiello et al, 2018; Pilz et al, 2019), or optic nerve hypoplasia (Kelberman et al, 2008).…”

SOX2 pathogenic variants with normal eyes: Expanding the phenotypic spectrum

“…At least 24 patients with heterozygous SOX2 pathogenic variants have been described in publications or genomic databases as having normal eyes in the presence of other features of SOX2 syndrome (Amlie‐Wolf et al, 2022; Bakrania et al, 2007; Blackburn et al, 2018; Chassaing et al, 2007; Dennert et al, 2017; Errichiello et al, 2018; Firth et al, 2009; Kelberman et al, 2006; Mihelec et al, 2009; Pilz et al, 2019; Shima et al, 2017; Stark et al, 2011; Takagi et al, 2014; Wang et al, 2008; Wang et al, 2022; Zenteno et al, 2006). On closer inspection, 11 of these patients had no ocular defects reported except for refractive errors or strabismus (Blackburn et al, 2018; Chassaing et al, 2007; Dennert et al, 2017; Firth et al, 2009; Stark et al, 2011; Wang et al, 2022; Zenteno et al, 2006), and on this basis, have been described in herein as having genuinely normal eyes. These are summarized in Table 1 along with our reported two patients.…”

“…As SOX2 is a single exon gene, these variants are not expected to invoke nonsense‐mediated mRNA decay (Bakrania et al, 2007; Ragge et al, 2005). Almost all SOX2 pathogenic variants reported to date appear to represent heterozygous loss of function, and thus it is difficult to determine any obvious genotype–phenotype correlation within this sub‐category of patients with normal eyes (Blackburn et al, 2018; Stark et al, 2011; Suzuki et al, 2014). Other reports have observed that identical pathogenic SOX2 variants can lead to ocular and extraocular defects of varying severity (Blackburn et al, 2018; Wang et al, 2022).…”

Genetic heterogeneity in corpus callosum agenesis

“…Mutations in other genes involved in the regulation of the Wnt/β-catenin signaling pathway have been reported in SOD cases: SOX2 (3q26.33) (OMIM 184429), SOX3 (Xq27.1) (OMIM 313430), OTX2 (14q22.3) (OMIM 600037), TCF7L1 (2p11.2) (OMIM 604652) or TAX1BP3 (17p13.2) (OMIM 616484). SOX2 mutations are associated with severe eye abnormalities, and additional features (genital anomalies, esophageal atresia, intellectual disability, seizures) (Blackburn et al, 2018). SOX3 duplications/point mutations have been reported in cases with hypopituitarism and/or intellectual disability (Arya et al, 2019;Li et al, 2022).…”