Mencarelli Maria Antonietta, Heidet Laurence, Storey Helen, van Geel Michel, Knebelmann Bertrand, Fallerini Chiara, Miglietti Nunzia, Antonucci Maria Fatima, Cetta Francesco, Sayer John A, van den Wijngaard Arthur, Yau Shu, Mari Francesca, Bruttini Mirella, Ariani Francesca, Dahan Karin, Smeets Bert, Antignac Corinne, Flinter Frances, Renieri Alessandra
Medical Genetics, University of Siena, Siena, Italy Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
APHP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Service de Néphrologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France.
J Med Genet. 2015 Mar;52(3):163-74. doi: 10.1136/jmedgenet-2014-102822. Epub 2015 Jan 9.
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.
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.
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.
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.
奥尔波特综合征是一种临床异质性进行性肾病，由胶原蛋白IV基因的突变引起，即2号染色体上的COL4A3和COL4A4以及X染色体上的COL4A5。广泛的表型变异性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疾病的遗传控制。因此，我们探讨了奥尔波特综合征受双基因控制的可能性。
我们使用大规模平行测序技术，鉴定出11名在两个胶原蛋白IV基因中存在致病突变的患者。对于每个先证者，我们在多达12名大家庭成员中确定了相同突变的存在，总共研究了56人。
总体而言，共发现23个突变。在不同基因中携带两个致病突变的个体，其肾功能恶化的平均年龄介于常染色体显性形式和常染色体隐性形式之间，这与IV型胶原三螺旋结构破坏的分子化学计量学一致。
分离分析表明了三种可能的双基因分离模型：（i）不同染色体上存在突变的常染色体遗传，类似于隐性遗传（5个家族）；（ii）同一染色体上存在突变的常染色体遗传，类似于显性遗传（2个家族）；以及（iii）不连锁的常染色体和X连锁遗传，具有特殊的分离方式（4个家族）。这种系谱分析为奥尔波特综合征的双基因遗传提供了证据。临床遗传学家和肾病学家应意识到这种可能性，以便更准确地评估遗传概率、预测预后并识别其他有风险的家庭成员。
