Hussain Hafiz Muhammad Jafar, Meng Wang, Li Yumei, Firasat Sabika, Pennesi Mark E, Gorin Michael B, Guan Bin, Clark Rebecca Lynn, Fale-Olsen Emma, Al Rawi Ranya, Agather Aime, Huryn Laryssa A, Yang Paul, Matynia Anna, Chen Rui
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Department of Ophthalmology, Center for Translational Vision Research, Irvine School of Medicine, University of California, Irvine, California, USA.
J Med Genet. 2025 Jul 31. doi: 10.1136/jmg-2025-110681.
Inherited retinal diseases (IRDs) are a group of disorders often resulting in progressive vision loss, ultimately leading to blindness. A significant portion of their genetic causes remain unresolved, partly due to undiscovered disease-associated genes or variants. This study aimed to identify novel genetic links to IRDs.
All patients underwent comprehensive ophthalmological evaluation, including retinal imaging (fundus autofluorescence and macular optical coherence tomography) and electroretinogram testing. Whole exome sequencing and whole genome sequencing were performed on patients with clinically unsolved IRD, and data were analysed using an in-house pipeline to identify causal variants. Subsequently, Sanger sequencing was performed to confirm identified variants.
Three unrelated patients from Europe, Middle East and East Asia were identified with unique late-onset retinal degeneration (Stargardt-like phenotype) associated with biallelic loss-of-function (LoF) variants in (HGNC: 26141), a gene of unknown function. The homozygous variant NM_032207.2:c.549_550del;p.Ser185Profs2 was identified in two unrelated patients (European and Middle Eastern). Moreover, an East Asian patient had likely compound heterozygous LoF variants (NM_032207.2:c.1168C>T;p.Gln390/c.976_977del;p.Leu326Lysfs*15).
Our findings establish as a novel disease-causing gene for IRD with Stargardt-like phenotype, expanding the genetic landscape of retinal degeneration.
遗传性视网膜疾病（IRDs）是一组常导致进行性视力丧失并最终导致失明的疾病。其很大一部分遗传原因仍未得到解决，部分原因是尚未发现与疾病相关的基因或变异。本研究旨在确定与IRDs的新遗传联系。
所有患者均接受了全面的眼科评估，包括视网膜成像（眼底自发荧光和黄斑光学相干断层扫描）和视网膜电图测试。对临床诊断未明确的IRD患者进行全外显子组测序和全基因组测序，并使用内部流程分析数据以识别致病变异。随后，进行桑格测序以确认所识别的变异。
来自欧洲、中东和东亚的三名无血缘关系的患者被确定患有独特的迟发性视网膜变性（类似Stargardt病的表型），与功能丧失性（LoF）双等位基因变异相关，该基因功能未知（HGNC：26141）。在两名无血缘关系的患者（欧洲人和中东人）中鉴定出纯合变异NM_032207.2:c.549_550del;p.Ser185Profs2。此外，一名东亚患者可能具有复合杂合LoF变异（NM_032207.2:c.1168C>T;p.Gln390/c.976_977del;p.Leu326Lysfs*15）。
我们的研究结果确定了该基因是具有类似Stargardt病表型的IRD的一种新致病基因，扩展了视网膜变性的遗传图谱。
