SOX2 and Anophthalmia/Microphthalmia-Esophageal Atresia Syndrome

SOX2 (HGNC:11195) encodes a high-mobility group transcription factor critical for early eye, foregut, and pituitary development. Heterozygous loss-of-function variants in SOX2 cause an autosomal dominant anophthalmia/microphthalmia-esophageal atresia syndrome (MONDO:0008799), characterized by severe bilateral eye malformations and esophageal atresia, often with additional neurological and genital anomalies.

Inheritance is autosomal dominant with the majority of pathogenic SOX2 alleles arising de novo. Over 26 unrelated probands have been reported with truncating SOX2 variants (e.g., frameshift or nonsense) across multiple cohorts (PMID:16543359, PMID:19921648, PMID:18831064). Segregation analysis identified variant transmission in four affected relatives—two sisters from a mosaic mother and two brothers in a germline mosaicism family (PMID:18831064, PMID:37885978).

The mutational spectrum is dominated by loss-of-function alleles, including recurrent deletions. The c.70_90del (p.Asn24_Ala30del) is the most frequent recurrent variant, accounting for approximately 20% of cases (PMID:26250054). Other reported variants include c.53C>A (p.Ser18Ter) and c.163C>T (p.Gln55Ter), all consistent with a haploinsufficiency mechanism.

Functional studies in human and model systems support pathogenicity via SOX2 haploinsufficiency. Mouse and zebrafish foregut expression assays demonstrate that reduced Sox2 dosage leads to esophageal malformations. In vitro, truncating mutants fail transactivation assays and disrupt Wnt–β-catenin regulation, concordant with human phenotypes (PMID:16543359, PMID:16932809).

No substantial conflicting evidence has been reported. Genotype-first screens in cohorts without ocular anomalies confirm that SOX2 is not a major cause of isolated intellectual disability or non-ocular phenotypes (PMID:27862890).

Collectively, the definitive genetic and experimental data establish SOX2 as the causative gene for AD anophthalmia/microphthalmia-esophageal atresia syndrome. Clinical SOX2 sequencing is recommended for diagnostic evaluation of patients presenting with bilateral anophthalmia or microphthalmia, especially when esophageal atresia is present.

Key Take-home: Heterozygous SOX2 loss-of-function variants cause definitive autosomal dominant anophthalmia/microphthalmia-esophageal atresia syndrome, with strong diagnostic and prognostic relevance.

References

• Human molecular genetics • 2006 • Mutations in SOX2 cause anophthalmia-esophageal-genital (AEG) syndrome. PMID:16543359
• The Journal of clinical investigation • 2006 • Mutations within Sox2/SOX2 are associated with abnormalities in the hypothalamo-pituitary-gonadal axis in mice and humans. PMID:16932809
• American journal of medical genetics. Part A • 2008 • Familial recurrence of SOX2 anophthalmia syndrome: phenotypically normal mother with two affected daughters. PMID:18831064
• Molecular vision • 2009 • Novel SOX2 mutations and genotype-phenotype correlation in anophthalmia and microphthalmia. PMID:19921648
• American journal of medical genetics. Part A • 2015 • SOX2 anophthalmia syndrome and dental anomalies. PMID:26250054
• International journal of reproductive biomedicine • 2023 • Prenatal diagnosis of Sex determining region Y -box transcription factor 2 anophthalmia syndrome caused by germline mosaicism using next-generation sequencing: A case report. PMID:37885978
• American journal of medical genetics. Part A • 2017 • De novo microdeletions and point mutations affecting SOX2 in three individuals with intellectual disability but without major eye malformations. PMID:27862890

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