PDF(Pubmed)
Abstract：
UNASSIGNED: Alport syndrome (AS) is a hereditary, progressive kidney disease characterized by structural abnormalities and dysfunction of the glomerular basement membrane (GBM). AS is classified as X-linked, autosomal, and digenic. The number of cases of digenic AS has increased, but the genotype-phenotype correlation of patient with digenic AS is still unclear. Here, we present a case of digenic AS with novel digenic missense variants in COL4A4 (c.827G>C, p.Gly276Ala) and COL4A5 (c.4369G>C, p.Gly1457Arg).
UNASSIGNED: The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman\'s capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in COL4A4 (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in COL4A5 (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient\'s paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved.
UNASSIGNED: The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.
UNASSIGNED: The patient was a 29-year-old Japanese man suffering from persistent microscopic hematuria and proteinuria without kidney function impairment. Kidney biopsy showed focal interstitial foam cell infiltration, global and segmental glomerulosclerosis. Immunofluorescence staining for collagen IV α5 was almost negative in the GBM and Bowman\'s capsule. Electron microscopy revealed irregular thickening with lamellation and segmental thinning of the GBM. Clinical and pathological findings were consistent with AS. Comprehensive next-generation sequencing revealed a heterozygous missense variant in COL4A4 (c.827G>C, p.Gly276Ala) in exon 1 and a hemizygous missense variant in COL4A5 (c.4369G>C, p.Gly1457Arg) in exon 49 on the patient\'s paternal and maternal alleles, respectively. The same digenic variants were detected in his sister, and she also showed a similar phenotype. After treatment with angiotensin-converting enzyme inhibitors, proteinuria decreased from 2.3 to 1.1 g/g creatinine, but occult blood persisted. During follow-up, kidney function has been preserved.
UNASSIGNED: The novel genotype of our case provides more information on the genotype-phenotype correlation of digenic XLAS, although long-term follow-up is required. The findings in the present case also indicate the importance of genetic tests for family members of a patient diagnosed with digenic AS.
摘要：
■Alport综合征（AS）是一种遗传性，以肾小球基底膜（GBM）结构异常和功能障碍为特征的进行性肾脏疾病。AS被归类为X连接，常染色体,和双重基因。双基因AS的病例数有所增加，但双基因AS患者的基因型-表型相关性尚不清楚。这里,我们提出了一个在COL4A4中具有新的双基因错义变异的双基因AS病例(c.827G>C，p.Gly276Ala）和COL4A5（c.4369G>C，p.Gly1457Arg)。
■患者是一名29岁的日本男性，患有持续性镜下血尿和蛋白尿，但没有肾功能损害。肾活检显示局灶性间质泡沫细胞浸润，全球性和节段性肾小球硬化。在GBM和Bowman's胶囊中，胶原蛋白IVα5的免疫荧光染色几乎为阴性。电子显微镜显示GBM的层状和节段变薄的不规则增厚。临床病理结果与AS一致。全面的下一代测序显示COL4A4中存在杂合错义变异（c.827G>C，p.Gly276Ala）在外显子1和COL4A5中的半合子错义变体（c.4369G>C，p.Gly1457Arg）在患者的父系和母系等位基因上的外显子49中，分别。在他妹妹身上也检测到了同样的双基因变异,她也表现出类似的表型。用血管紧张素转换酶抑制剂治疗后，蛋白尿从2.3g/g肌酐下降到1.1g/g肌酐，但潜血仍然存在。随访期间,肾功能得以保留。
■我们病例的新基因型提供了有关双基因XLAS的基因型-表型相关性的更多信息，虽然需要长期随访。本案的发现还表明，对诊断为双基因AS的患者的家庭成员进行基因检测的重要性。
■患者是一名29岁的日本男性，患有持续性镜下血尿和蛋白尿，但没有肾功能损害。肾活检显示局灶性间质泡沫细胞浸润，全球性和节段性肾小球硬化。在GBM和Bowman's胶囊中，胶原蛋白IVα5的免疫荧光染色几乎为阴性。电子显微镜显示GBM的层状和节段变薄的不规则增厚。临床病理结果与AS一致。全面的下一代测序显示COL4A4中存在杂合错义变异（c.827G>C，p.Gly276Ala）在外显子1和COL4A5中的半合子错义变体（c.4369G>C，p.Gly1457Arg）在患者的父系和母系等位基因上的外显子49中，分别。在他妹妹身上也检测到了同样的双基因变异,她也表现出类似的表型。用血管紧张素转换酶抑制剂治疗后，蛋白尿从2.3g/g肌酐下降到1.1g/g肌酐，但潜血仍然存在。随访期间,肾功能得以保留。
■我们病例的新基因型提供了有关双基因XLAS的基因型-表型相关性的更多信息，虽然需要长期随访。本案的发现还表明，对诊断为双基因AS的患者的家庭成员进行基因检测的重要性。
