Supplementary Material for: Trigenic COL4A3/COL4A4/COL4A5 pathogenic variants in Alport syndrome: a case report

Alport syndrome (AS) is a hereditary kidney disorder of type IV collagen caused by pathogenic variants in the COL4A3, COL4A4 and COL4A5 genes. Previously several cases of digenic AS, caused by two pathogenic variants in two of the three COL4A genes, have been reported. Patients with digenic AS may present with a more severe phenotype compared to patients with single variants, depending on the percentage affected type IV trimeric collagen chain. We report a newly discovered case of trigenic AS.
A 52-year-old female presented with hematuria at the age of 24 years and developed hypertension by the age of 30. Over the years she developed chronic kidney disease; the most recent eGFR was 44ml/min/1.73m2. She has symmetric high-tone sensorineural hearing loss. Full genetic analysis revealed a heterozygous pathogenic variant c.2691del in COL4A3, a heterozygous pathogenic variant c.1663dup in COL4A4, and a complete heterozygous deletion of COL4A5.
We describe the first patient with AS caused by pathogenic variants in all three COL4A genes, designated trigenic AS. This case report emphasizes the importance of examining all three COL4A genes, even in patients with a mild Alport phenotype, for optimal follow-up of the patient and adequate genetic counseling of family members.

奥尔波特综合征（Alport syndrome，AS）是一类由COL4A3、COL4A4及COL4A5基因发生致病性变异导致的IV型胶原蛋白（type IV collagen）遗传性肾病。既往已有多例双基因性AS（digenic AS）的报道，这类病例由三个COL4A基因中的两个基因各携带一个致病性变异所引发。相较于仅携带单个变异的患者，双基因性AS患者的表型可能更为严重，具体严重程度取决于受累的IV型胶原三聚体链的占比。本次我们报道一例新发现的三基因性AS（trigenic AS）病例。
患者为52岁女性，24岁时出现血尿（hematuria），30岁时进展为高血压（hypertension）。随病程发展，患者出现慢性肾脏病（chronic kidney disease）；最近一次检测的估算肾小球滤过率（eGFR）为44ml/min/1.73m²。患者存在对称性高频性感音神经性听力损失（sensorineural hearing loss）。全面基因分析显示，其COL4A3基因存在c.2691del杂合致病性变异（heterozygous pathogenic variant），COL4A4基因存在c.1663dup杂合致病性变异，同时COL4A5基因存在完全杂合缺失（complete heterozygous deletion）。
本次报道的是首例由三个COL4A基因均携带致病性变异引发的AS病例，我们将其命名为三基因性AS（trigenic AS）。本病例报告强调，即便患者表现为轻度奥尔波特综合征表型，也应对全部三个COL4A基因进行检测，以实现患者的最优随访及为家庭成员提供充分的遗传咨询（genetic counseling）。