Novel frameshift variant in gene SALL4 causing Okihiro syndrome

Area of Science:

• Genetics
• Developmental Biology
• Medical Genetics

Background:

• Okihiro syndrome, also known as Duane-radial ray syndrome, is a rare, autosomal dominant disorder.
• It is characterized by upper limb radial defects and Duane anomaly, caused by variants in the SALL4 gene.

Purpose of the Study:

• To report a novel heterozygous frameshift variant (c.410dupG) in the SALL4 gene within a Brazilian family.
• To investigate the genotype-phenotype correlation in Okihiro syndrome, particularly concerning limb and foot malformations.

Main Methods:

• Genetic sequencing to identify variants in the SALL4 gene.
• Clinical evaluation of affected individuals to document phenotypic variability.
• Bioinformatic prediction of the variant's effect on the SALL4 protein.

Main Results:

• A novel SALL4 frameshift variant, c.410dupG, was identified in five affected family members with a spectrum of phenotypes.
• Observed phenotypes ranged from severe limb deformities to less conspicuous thumb abnormalities; Duane's anomaly was absent.
• The variant is predicted to produce a truncated SALL4 protein, similar in size to that from a previously reported variant, yet with distinct phenotypic presentations.

Conclusions:

• The study identified a new SALL4 variant associated with Okihiro syndrome, emphasizing the condition's extreme phenotypic variability.
• A potential correlation between severe foot malformations and SALL4 variants predicted to produce truncated proteins lacking seven zinc finger motifs is suggested.
• Establishing a direct genotype-phenotype correlation for SALL4 variants remains challenging due to observed phenotypic diversity.