SALL4 – Duane Retraction Syndrome

Duane retraction syndrome (DRS) is a congenital ocular motility disorder characterized by impaired abduction, globe retraction, and variable palpebral fissure narrowing on adduction. SALL4 encodes a zinc-finger transcription factor essential for embryonic development, and truncating SALL4 variants are established causes of Okihiro syndrome. Emerging case-level and cohort data suggest that heterozygous loss-of-function alleles in SALL4 also underlie isolated autosomal dominant DRS. Using the ClinGen framework, the gene–disease association is currently rated as Limited.

In a non-consanguineous Chinese Han pedigree, a novel heterozygous duplication, c.1919dup (p.Met640IlefsTer25), was identified in all affected members and absent in 200 controls, with complete cosegregation across at least three meioses (PMID:23687435). This frameshift is predicted to induce nonsense-mediated decay and truncate both central and C-terminal zinc-finger domains.

In a prospective screening of 72 South Indian patients with isolated or syndromic DRS, no coding or splice-site SALL4 variants were detected, highlighting genetic heterogeneity in DRS pathogenesis (PMID:21405998). This negative cohort suggests that SALL4 mutations account for only a subset of DRS cases.

A recent retrospective study of 42 Han Chinese DRS patients identified a de novo splice-acceptor variant, c.1432-2A>T, in a DRS1 proband with MRI-documented abducens nerve aplasia (PMID:40212284). This finding extends the variant spectrum to non-coding splice-site mutations and reinforces a haploinsufficiency mechanism.

Both frameshift and splice-site alterations are predicted to result in SALL4 haploinsufficiency. Although no DRS-specific functional assays have been reported, existing data from Okihiro syndrome support loss-of-function as a pathogenic mechanism. No genotype–phenotype correlation with variant position has been established.

In summary, two unrelated probands with heterozygous truncating or splice variants, one with clear familial segregation and one de novo, provide preliminary evidence linking SALL4 to isolated autosomal dominant DRS. However, absence of variants in a large cohort and lack of functional validation limit the current evidence to a Limited strength level. Genetic testing for SALL4 should be considered in familial or de novo DRS1 presentations. Additional case series and functional studies are required to confirm and refine this association.

References

• Molecular vision • 2013 • Diversified clinical presentations associated with a novel sal-like 4 gene mutation in a Chinese pedigree with Duane retraction syndrome. PMID:23687435
• Ophthalmic genetics • 2011 • Analysis of the SALL4 gene in patients with Duane retraction syndrome in a South Indian population. PMID:21405998
• Frontiers in genetics • 2025 • Etiology and clinical features of Han Chinese patients with Duane retraction syndrome. PMID:40212284

Evidence Based Scoring (AI generated)