Kong Qiaoqiao, Lu Xuejing
Eye School of Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Front Med (Lausanne). 2025 Aug 5;12:1624093. doi: 10.3389/fmed.2025.1624093. eCollection 2025.
Genome-wide association studies have identified key roles for specific genes in ocular axis elongation and related complications in pathological myopia (PM). In this study, we conducted a comprehensive genetic analysis of a family with a high prevalence of PM to identify novel genetic loci associated with PM, aiming to inform clinical practice.
Genomic DNA was extracted from oral swabs of the proband and family members for sequencing.
A RHO gene variant (NM_000539.3:exon1:c.61C > T:p.R21C) was identified in the proband, potentially associated with the clinical phenotype. Her eldest sister carried the wild-type allele, while her second sister was heterozygous at the validation locus. Further investigation revealed a clustering of female patients with high myopia among the patient's maternal siblings and their offspring. Therefore, we extended our study to include maternal relatives with axial lengths greater than 26 mm and highly myopic features to identify potential genetic loci. However, exome high-throughput sequencing did not detect any pathogenic variants. Given that the proband's mother was deceased, whole-exome sequencing was performed on her father and her second sister, who had more severe conditions. No variants were found that could explain the observed clinical phenotype. Thus, we hypothesized that the proband's mother might carry a gonadal chimeric variant.
The clinical significance of the RHO gene variant (NM_000539.3:exon1:c.61C > T:p.R21C) in our family remains unclear, and the variant is classified as a variant of uncertain significance. Although this RHO variant may potentially be associated with the observed phenotype, further evidence is required to establish a definitive correlation. Based on the available data, gonadal mosaicism represents the most plausible explanatory model; however, this hypothesis cannot be considered conclusive at this stage.
全基因组关联研究已经确定了特定基因在病理性近视（PM）眼轴伸长及相关并发症中的关键作用。在本研究中，我们对一个PM高发家族进行了全面的基因分析，以确定与PM相关的新基因位点，旨在为临床实践提供依据。
从先证者和家庭成员的口腔拭子中提取基因组DNA进行测序。
在先证者中鉴定出一个RHO基因变体（NM_000539.3:exon1:c.61C>T:p.R21C），可能与临床表型相关。她的大姐携带野生型等位基因，而二姐在验证位点为杂合子。进一步调查发现，患者母亲的兄弟姐妹及其后代中高度近视女性患者聚集。因此，我们扩大研究范围，纳入眼轴长度大于26mm且具有高度近视特征的母系亲属，以确定潜在的基因位点。然而，外显子高通量测序未检测到任何致病变体。鉴于先证者的母亲已去世，对她病情更严重的父亲和二姐进行了全外显子测序。未发现能够解释观察到的临床表型的变体。因此，我们推测先证者的母亲可能携带性腺嵌合变体。
我们家族中RHO基因变体（NM_000539.3:exon1:c.61C>T:p.R21C）的临床意义尚不清楚，该变体被分类为意义未明的变体。虽然这个RHO变体可能与观察到的表型潜在相关，但需要进一步证据来建立明确的相关性。根据现有数据，性腺嵌合现象是最合理的解释模型；然而，在现阶段这一假设不能被视为定论。
