Evidence of digenic inheritance in Alport syndrome
Evidence of digenic inheritance in Alport syndrome
复制标题
DOI：
10.1136/jmedgenet-2014-102822
复制
发表时间：
2015-03-01
影响因子：
4
通讯作者：
Renieri, Alessandra
中科院分区：
文献类型：
--
作者：
Mencarelli, Maria Antonietta;Heidet, Laurence;Renieri, Alessandra
Alport综合征是一种临床异质性的进行性肾病，由胶原IV基因突变引起，即2号染色体上的COL4A3和COL4A4以及x号染色体上的COL4A5。广泛的表型变异和不完全外显率的存在表明简单的孟德尔模型不能完全解释该病的遗传控制。因此，我们探讨了Alport综合征受基因控制的可能性。方法采用大规模平行测序技术，鉴定了11例两种IV型胶原基因发生致病性突变的患者。对于每个先证者，我们确定了相同突变在多达12个大家庭成员中存在，总共研究了56人。结果共发现23个突变。不同基因中具有两种致病突变的个体，其肾功能恶化的平均年龄相对于常染色体显性型和常染色体隐性型处于中等水平，这与IV型胶原三螺旋破坏的分子化学计量学一致。结论分离分析显示三种可能的基因分离模式：(1)常染色体遗传，不同染色体发生突变，类似于隐性遗传（5个家族）；（ii）常染色体遗传，同一染色体上的突变类似于显性遗传（两个家族）；（iii）非连锁常染色体遗传和x连锁遗传，具有特殊的分离（四个家族）。本家谱分析为阿尔波特综合征的基因遗传提供了证据。临床遗传学家和肾病学家应该意识到这种可能性，以便更准确地评估遗传概率，预测预后并确定其他有风险的家庭成员。
Background Alport syndrome is a clinically heterogeneous, progressive nephropathy caused by mutations in collagen IV genes, namely COL4A3 and COL4A4 on chromosome 2 and COL4A5 on chromosome X. The wide phenotypic variability and the presence of incomplete penetrance suggest that a simple Mendelian model cannot completely explain the genetic control of this disease. Therefore, we explored the possibility that Alport syndrome is under digenic control.Methods Using massively parallel sequencing, we identified 11 patients who had pathogenic mutations in two collagen IV genes. For each proband, we ascertained the presence of the same mutations in up to 12 members of the extended family for a total of 56 persons studied.Results Overall, 23 mutations were found. Individuals with two pathogenic mutations in different genes had a mean age of renal function deterioration intermediate with respect to the autosomal-dominant form and the autosomal-recessive one, in line with molecule stoichiometry of the disruption of the type IV collagen triple helix.Conclusions Segregation analysis indicated three possible digenic segregation models: (i) autosomal inheritance with mutations on different chromosomes, resembling recessive inheritance (five families); (ii) autosomal inheritance with mutations on the same chromosome resembling dominant inheritance (two families) and (iii) unlinked autosomal and X-linked inheritance having a peculiar segregation (four families). This pedigree analysis provides evidence for digenic inheritance of Alport syndrome. Clinical geneticists and nephrologists should be aware of this possibility in order to more accurately assess inheritance probabilities, predict prognosis and identify other family members at risk.