Genotype-phenotype profile of global ASPH-associated ectopia lentis and clinical findings from a Chinese cohort

• Published in: Gene 2024-10, Vol.925, p.148600, Article 148600
• Main Authors: Chen, Ze-Xu, Jia, Wan-Nan, Sun, Yang, Jiang, Yong-Xiang
• Format: Article
• Language: English
• Subjects: ASPH; Ectopia lentis; Genotype-phenotype correlation; Single-cell RNA-sequencing; Traboulsi syndrome
• ISSN: 0378-1119; 1879-0038; 1879-0038
• DOI: 10.1016/j.gene.2024.148600

•We identified a novel missense variant c.2075G > A and a recurrent nonsense variant c.1126C > G of ASPH in two pedigrees.•The single-cell expression atlas demonstrated coexpression of ASPH with FBN1, FBN2, and LTBP2 in non-pigmented ciliary epithelial cells.•Molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and destabilization of the calcium-binding motif.•Genotype-phenotype analysis revealed that patients with cardiac involvement all harbored biallelic truncation variants. Traboulsi syndrome is an under-recognized syndromic form of ectopia lentis (EL) caused by the aspartate beta-Hydroxylase (ASPH) variant. The genotype-phenotype profile of ASPH-associated disease is poorly understood due to the rarity of the condition. We conducted targeted next-generation sequencing and bioinformatics analysis to identify potentially pathogenic ASPH variants in the cohort. Furthermore, we characterized the expression pattern of ASPH and major components of the zonules using single-cell RNA-sequencing (scRNA-seq) and evaluated the genotype-phenotype correlations by combining our data and those from the literature. We identified a novel missense variant c.2075G > A (p.G692D) and a recurrent nonsense variant c.1126C > G (p.R376*) of ASPH in two pedigrees from a Chinese cohort of EL. Both probands were 5-year-old boys with canonical facial dysmorphisms and bilateral anteriorly-dislocated lenses. Other ocular comorbidities included microspherophakia, shallow anterior chamber, and narrow chamber angel. No cardiac involvements or filtering blebs were identified. The single-cell expression atlas of ciliary epithelium demonstrated the coexpression of ASPH with FBN1, FBN2, and LTBP2 in the non-pigmented ciliary epithelium cells. Furthermore, molecular modeling simulation of p.G692D revealed increased affinity to the cb EGF-like domain and a subsequent destabilized calcium-binding motif. The genotype-phenotype analysis demonstrated that patients with cardiac involvements all harbored biallelic truncation variants. The data from this study provide new insights into the genotype-phenotype profile of ASPH-associated disease and implicate the potential role of ASPH in the pathogenesis of EL.