Abstract：
Thin basement membrane nephropathy (TBMN) is characterized by the observation of microhematuria and a thin glomerular basement membrane on kidney biopsy specimens. Its main cause is heterozygous mutations of COL4A3 or COL4A4, which also cause late-onset focal segmental glomerulosclerosis (FSGS) or autosomal dominant Alport syndrome (ADAS). Thirteen TBMN cases were analyzed using Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and exome sequencing. Ten heterozygous variants were detected in COL4A3 or COL4A4 in nine patients via Sanger sequencing, three of which were novel variants. The diagnostic rate of \"likely pathogenic\" or \"pathogenic\" under the American College of Medical Genetics and Genomics guidelines was 53.8% (7 out of 13 patients). There were eight single nucleotide variants, seven of which were glycine substitutions in the collagenous domain, one of which was a splice-site single nucleotide variant, and two of which were deletion variants. One patient had digenic variants in COL4A3 and COL4A4. While MLPA analyses showed negative results, exome sequencing identified three heterozygous variants in causative genes of FSGS in four patients with no apparent variants on Sanger sequencing. Since patients with heterozygous mutations of COL4A3 or COL4A4 showed a wide spectrum of disease from TBMN to ADAS, careful follow-up will be necessary for these patients.
摘要：
薄基底膜肾病（TBMN）的特征是在肾脏活检标本上观察到微血尿和薄的肾小球基底膜。其主要原因是COL4A3或COL4A4的杂合突变，这也会导致迟发性局灶性节段肾小球硬化（FSGS）或常染色体显性遗传Alport综合征（ADAS）。13例TBMN病例采用Sanger测序进行分析，多重连接依赖性探针扩增（MLPA），和外显子组测序。通过Sanger测序，在9名患者的COL4A3或COL4A4中检测到10个杂合变体，其中三个是新颖的变体。根据美国医学遗传学和基因组学学院指南，“可能致病”或“致病”的诊断率为53.8％（13例患者中有7例）。有八种单核苷酸变异,其中七个是胶原域中的甘氨酸取代，其中之一是剪接位点单核苷酸变异，其中两个是缺失变体。一名患者在COL4A3和COL4A4中有双基因变异。虽然MLPA分析显示阴性结果，外显子组测序在4例患者的FSGS致病基因中发现了3种杂合变异,但在Sanger测序中没有明显变异.由于具有COL4A3或COL4A4杂合突变的患者表现出从TBMN到ADAS的广泛疾病，这些患者需要仔细的随访。
