SOX2-Related Ocular Disorders via the SOX2 Gene

Congenital ocular malformations: anophthalmia (A; absence of a globe in the orbit) and microphthalmia (M; reduced size of the globe) are severe and rare developmental defects of the globe with an estimated incidence of 0.2–0.4/10 000 and ~1.5/10 000 live births, respectively (Källén and Tornqvist 2005). Both A/M may be unilateral or bilateral, and over 50% of A/M affected individuals have systemic abnormalities such as hypothalamic–pituitary disorder, mild dysmorphic facial features and short stature, urogenital anomalies, cryptorchidism and/or micropenis in males, developmental delay, seizures, oesophageal atresia or tracheooesophageal fistula and hearing loss (Ragge et al. 2005), but only 25% of these are part of distinct and well-defined syndromes (Bakrania et al. 2007). Unilateral A/M cases often have developmental anomalies of the other eye; including coloboma, lens, and optic nerve (Ragge et al. 2007).

A/M has a complex aetiology with a wide range of causes, including chromosomal abnormalities, as well as environmental factors (Pedace et al. 2009). Chromosomal duplications, deletions and translocations account for 23–30% of A/M cases. Bakrania et al. reported whole SOX2 gene deletions in ~10% of their A/M patients cohort (Bakrania et al. 2007), which emphasizes the necessity of careful chromosomal analysis (particularly the 3q region that comprises the SOX2 gene) (Guichet et al. 2004). Of monogenic causes, only SOX2 [Sex determining region Y (SRY)-box 2] has been identified as a major causative gene in which heterozygous, loss of function mutations account for 10–20% of the A/M cases (Reis et al. 2010; Faivre et al. 2006; Ragge et al. 2005; Williamson 2006). Other A/M associated genes include PAX6, SIX6, HESX1, BCOR, SHH, RAX, CHD7, IKBKG, NDP, POMT1, GDF6, VSX2 and SIX3 (Bardakjian et al. 2006; Slavotinek 2011). SOX2-related ocular disorder is inherited in an autosomal dominant manner, and the majority of the causative SOX2 sequence variations are de novo (FitzPatrick 2009). Occasional cases result from parental gonosomal mosaicism (Faivre et al. 2006; Schneider et al. 2008).

Sox2 is a member of the Sox family of proteins, which encodes an SRY-like HMG (High Mobility Group) box transcription factor. The HMG domain among Sox proteins is highly conserved and is critical for correct binding to interacting proteins (Williamson 2006). Sox2 plays a key regulatory role in lens development and is reported to interact with Oct-1 and Pax6 to control lens and nasal placode development (Kamachi et al. 2001; Donner et al. 2007).

A mutation analysis in a cohort of 120 patients with congenital eye abnormalities, mainly A/M and coloboma, identified pathogenic variations in the coding region of the SOX2 gene in 6 patients and whole gene deletions in 5 patients (Bakrania et al. 2007). Another mutation screening in a cohort of 51 unrelated individuals affected with bilateral (38) or unilateral (13) A/M revealed SOX2 mutations in ten patients (19.6%). Seven of them had novel alterations, while the remaining three individuals had previously reported a recurrent 20-nucleotide deletion designated c.70_89del20. This deletion accounts for 30% of SOX2 mutations in their cohort (Schneider et al. 2009) and ~21% of all SOX2 cases that have been reported to date (Reis et al. 2010).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the SOX2 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.