Identification of a novel single nucleotide deletion in the NHS causing Nance-Horan syndrome.

BACKGROUND: Nance-Horan syndrome (NHS) is a rare X-linked dominant disorder caused by pathogenic variants in the NHS gene on chromosome Xp22.2-Xp22.13. Clinical manifestations consist of congenital cataracts, along with dysmorphic facial features and dental anomalies and, in certain instances, intellectual disability. This study aimed to identify the genetic cause responsible for NHS in a Chinese family with four individuals primarily presenting with congenital cataracts. METHODS: Genomic DNA was collected from six family members, including four affected individuals (three females and one male) from a two-generation family. The family history and clinical data were documented. Whole-exome sequencing was performed on the proband, and candidate pathogenic variants were filtered through a series of screening steps and validated by Sanger sequencing. Co-segregation analysis was conducted to confirm the pathogenicity of the identified variant. RESULTS: Genetic analysis revealed a novel frameshift pathogenic variant in NHS gene (c.1735delA: p.R579Gfs*91) present in all four affected members. All affected members exhibited congenital cataracts, congenital ptosis, strabismus, high myopia as well as dental and facial anomalies, and more severe characteristic features observed in the male patient. These clinical manifestations were consistent with the phenotype of NHS. CONCLUSION: This study identified a novel NHS pathogenic variant in a Chinese family, expanding the mutational spectrum of NHS. Contrary to previous reports of female carriers exhibiting mild symptoms, we demonstrated severe ocular phenotypes in three affected females. These findings will assist in providing genetic counseling for NHS patients.