Genetic analysis of Han-Chinese patients with isolated congenital ptosis

To conduct a genetic analysis of Han-Chinese patients with isolated congenital ptosis (ICP) and identify the genetic variants related to the condition.

Sixty-five unrelated patients with ICP were enrolled. Comprehensive clinical examinations, whole exome sequencing (WES), and Sanger sequencing were used to reveal the potential genetic causes. Combined with public and in-house control databases, multiple bioinformatics prediction tools, and conservation analysis, the potential variants were further analyzed. AlphaFold 3, an accurate modelling prediction tool, was utilized to generate three-dimensional structural models of both wild-type and mutated proteins.

Three novel heterozygous variants in the zinc finger homeobox 4 gene (ZFHX4), c.5145C>A (p.N1715K), c.10382C>T (p.A3461V), and c.10795G>A (p.A3599T), were identified in three patients, respectively. Bioinformatics analyses suggested that these variants are likely to exert deleterious effects, supporting their potential involvement in the pathogenesis of ptosis.

The novel heterozygous ZFHX4 variants are identified as disease-associated variants in three patients with ptosis, suggesting that ZFHX4 may be a disease-causing gene for autosomal dominant ICP with incomplete penetrance or a susceptibility gene. These findings expand the variant spectrum of ZFHX4, improve understanding of the pathogenesis of ZFHX4-related ptosis, and may contribute to the genetic counseling and disease management, as well as the development of experimental treatments.