Clinical characteristics and genetic etiology of a Chinese pedigree with MFRP-associated nanophthalmos

Objective  To explore the clinical characteristics and genetic etiology of a Chinese Hui family with nanophthalmos.

Methods  A pedigree investigation was performed.The clinical features and genetic etiology analysis were conducted in this Chinese family with nanophthalmos who first visited Beijing Tongren Eye Center in October 2005 and were followed up until October 2023.This family included 25 individuals of 4 generations, among which there were 3 patients.All the patients underwent medical history collection and comprehensive ophthalmological examinations, including visual acuity, intraocular pressure, slit-lamp microscope, IOLMaster, ultrasound biomicroscopy, color fundus photography, B-scan ultrasonography, visual field, etc.Genomic DNA was extracted from the 3 patients and 3 phenotypically normal individuals.Disease-causing genes were screened by whole-exome sequencing.Bioinformatic analysis and prediction of pathogenicity of candidate variants were conducted, followed by further validation by Sanger sequencing and co-segregation analysis.All the included subjects were informed of the purpose and methods of the study and signed an informed consent form.The study protocol was reviewed and approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (No.TRECKY2021-241).

Results  Nanophthalmos in this family was inherited in an autosomal recessive manner.The proband and his two sisters were diagnosed with nanophthalmos based on clinical evaluation of typical phenotypes including the reduction of visual acuity, hyperpresbyopia, short ocular axis, shallow anterior chamber, narrow anterior chamber angle, high intraocular pressure, crowded optic disc, tortuous retinal vessel, etc.companied by angle-closure glaucoma, exudative retinal detachment and uveal effusion and other common complications.Compound heterozygous variants c. 1010_1021del (p.His337_Glu340del) and c. 1486G>A (p.Glu496Lys) were detected in MFRP gene in all three patients, and c. 1010_1021del, one of the biallelic variants was first reported.Both variants were rare in healthy populations and were co-segregated within this pedigree.According to the standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, the variants were predicted to have strong pathogenicity and were the genetic cause of the nanophthalmos in this pedigree.

Conclusions  This study finds a novel pathogenic variant c.1010_1021del in a nanophthalmos pedigree.

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