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

Abstract

SOX2 variants and deletions are a common cause of anophthalmia and microphthalmia (A/M). This article presents data from a cohort of patients with SOX2 variants, some of whom have been followed for 20+ years. Medical records from patients enrolled in the A/M Research Registry and carrying SOX2 variants were reviewed. Thirty‐seven patients were identified, ranging in age from infant to 30 years old. Eye anomalies were bilateral in 30 patients (81.1%), unilateral in 5 (13.5%), and absent in 2 (5.4%). Intellectual disability was present in all with data available and ranged from mild to profound. Seizures were noted in 18 of 27 (66.6%) patients, usually with abnormal brain MRIs (10/15, 66.7%). Growth issues were reported in 14 of 21 patients (66.7%) and 14 of 19 (73.7%) had gonadotropin deficiency. Genitourinary anomalies were seen in 15 of 19 (78.9%) male patients and 5 of 15 (33.3%) female patients. Patients with SOX2 nucleotide variants, whole gene deletions or translocations are typically affected with bilateral or unilateral microphthalmia and anophthalmia. Other associated features include intellectual disability, seizures, brain anomalies, growth hormone deficiency, gonadotropin deficiency, and genitourinary anomalies. Recommendations for newly diagnosed patients with SOX2 variants include eye exams, MRI of the brain and orbits, endocrine and neurology examinations. Since the clinical spectrum associated with SOX2 alleles has expanded beyond the originally reported phenotypes, we propose a broader term, SOX2‐associated disorder, for this condition.

Novel Genetic Diagnoses in Septo-Optic Dysplasia

“…SOX2 intragenic variants and deletions are the most common cause of anophthalmia/microphthalmia, typically syndromic with commonly seen esophageal, genitourinary, and neurological anomalies [ 5 ]. A connection to SOD was noted in a mouse model, and subsequent screening in a cohort of individuals with SOX2 variants identified pituitary hypoplasia and hypogonadotropic hypogonadism along with anomalies of the corpus callosum and medial temporal structures [ 6 ].…”

“…Individual 1 of this study is the first case of SOD with normal eye size and a lack of additional birth defects to have a loss-of-function variant in SOX2 . Interestingly, the identified SOX2 variant, c.70_89del, is a recurrent variant now reported in 20 individuals; while the majority of cases presented with a severe phenotype of syndromic anophthalmia/microphthalmia, phenotypic variability has been reported in some cases [ 5 ]. An abnormal gait, often described as ataxic and requiring the use of a walker or other assistive devices, is typical for SOX2 disruption [ 5 ].…”

Novel SOX2 mutation in autosomal dominant cataract-microcornea syndrome

“…Sox2 is involved in crystallin regulation in murine [ 22 ] and avian models [ 23 ] and humans, and SOX2 mutations cause microphthalmia and cataracts [ 24 , 25 ]. Previously, 21 of 37 patients with anophthalmia and microphthalmia carried frameshift and deletion/translocation mutations in the SOX2 gene [ 26 ]. In terms of missense mutations, only 2 of 37 patients with microphthalmia carried missense mutations, c.131C > G and c.166C > G [ 26 , 27 ], indicating that phenotype released from deletion missense mutation.…”

“…Previously, 21 of 37 patients with anophthalmia and microphthalmia carried frameshift and deletion/translocation mutations in the SOX2 gene [ 26 ]. In terms of missense mutations, only 2 of 37 patients with microphthalmia carried missense mutations, c.131C > G and c.166C > G [ 26 , 27 ], indicating that phenotype released from deletion missense mutation. Interestingly, a missense mutation in this study, SOX2 c.295G > T p.Ala99Ser, caused a slight phenotype: microcornea and cataract.…”

Heterozygous mutations in SOX2 may cause idiopathic hypogonadotropic hypogonadism via dominant-negative mechanisms

“…Pathogenic mutations in the SOX2 gene (encoding the SRY-related HMG-box 2 transcription factor protein) were initially identified as a monogenic cause for anophthalmia/microphthalmia (A/M) ( 1 ). Over the last 2 decades, it has become apparent that the phenotypic spectrum relating to SOX2 mutations extends beyond A/M ( 2 ) to encompass a spectrum of other ocular defects (coloboma, optic nerve hypoplasia, hypertelorism, short palpebral fissure) and even broader extraocular phenotypes, such as neurocognitive delay, intellectual disability, brain anomalies, seizures, pituitary dysfunction, hypogonadotropic hypogonadism, genital anomalies, sensorineural hearing loss, and esophageal atresia ( 1 ). This expanded spectrum has led to the suggestion that this syndrome be referred to as a SOX2 -associated disorder ( 1 ).…”