Rare Diseases Centre, Medical University of Gdańsk, Gdańsk, Poland; Department of Pediatrics, Nephrology and Hypertension, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
Department of Pediatrics, Nephrology and Hypertension, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland.
Kidney Int. 2021 Jun;99(6):1451-1458. doi: 10.1016/j.kint.2020.10.040. Epub 2020 Dec 10.
A study of 269 children enrolled into a National Registry for children with persistent glomerular hematuria identified 131 individuals with genetically confirmed X-linked Alport Syndrome. A single variant c.1871G>A p.Gly624Asp (G624D) in COL4A5 was predominant and accounted for 39% of X-linked Alport Syndrome in unrelated Polish families (44 of 113). To evaluate its origins, the genetic variation in a 2.79 Mb segment encompassing the COL4A5 locus on chromosome X was assessed. All G624D alleles were found on the same rare haplotype background, indicating a founder effect dating back to the 12-13th century. The phenotypic data of 131 children with X-linked Alport Syndrome and their 195 affected adult relatives revealed that the G624D variant was associated with a significantly milder clinical course in comparison to other pathogenic COL4A5 variants. Furthermore the clinical course of this genetically uniform cohort was milder than that observed in individuals with other COL4A5 missense mutations. In spite of the benign clinical manifestation throughout childhood and early adulthood, the G624D variant confers significant risk for both kidney failure and deafness in males, albeit 20-30 years later than that observed in individuals with other COL4A5 pathogenic variants (50% cumulative risk of starting dialysis at 54 years (95% confidence interval: 50-62) v. 26 years (95% confidence interval: 22-30)). Thus, males with G624D are candidates for existing and emerging therapies for Alport Syndrome.
一项针对 269 名患有持续性肾小球血尿的儿童进行的全国登记研究，确定了 131 名经基因证实的 X 连锁 Alport 综合征患者。COL4A5 中的单一变异 c.1871G>A p.Gly624Asp（G624D）占无关波兰家族中 X 连锁 Alport 综合征的 39%（113 例中的 44 例）。为了评估其起源，评估了涵盖 X 染色体上 COL4A5 基因座的 2.79Mb 片段中的遗传变异。在同一罕见单倍型背景下发现了所有 G624D 等位基因，表明这是一种可以追溯到 12-13 世纪的创始人效应。对 131 名 X 连锁 Alport 综合征患儿及其 195 名受累成年亲属的表型数据进行分析，结果表明与其他致病性 COL4A5 变异相比，G624D 变异与更轻微的临床病程相关。此外，该遗传一致队列的临床病程比其他 COL4A5 错义突变个体观察到的更轻。尽管在儿童和成年早期的临床表现为良性，但 G624D 变异会使男性患肾衰竭和耳聋的风险显著增加，尽管比其他 COL4A5 致病性变异患者晚 20-30 年（50%累积风险在 54 岁（95%置信区间：50-62）开始透析，而 26 岁（95%置信区间：22-30））。因此，G624D 男性是 Alport 综合征现有和新兴疗法的候选者。
