Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.
Consensus statement on standards and guidelines for the molecular diagnostics of Alport syndrome: refining the ACMG criteria.
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DOI：
10.1038/s41431-021-00858-1
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发表时间：
2021-08
期刊：
影响因子：
--
通讯作者：
Lipska-Ziętkiewicz BS
中科院分区：
文献类型：
--
作者：
Savige J;Storey H;Watson E;Hertz JM;Deltas C;Renieri A;Mari F;Hilbert P;Plevova P;Byers P;Cerkauskaite A;Gregory M;Cerkauskiene R;Ljubanovic DG;Becherucci F;Errichiello C;Massella L;Aiello V;Lennon R;Hopkinson L;Koziell A;Lungu A;Rothe HM;Hoefele J;Zacchia M;Martic TN;Gupta A;van Eerde A;Gear S;Landini S;Palazzo V;Al-Rabadi L;Claes K;Corveleyn A;Van Hoof E;van Geel M;Williams M;Ashton E;Belge H;Ars E;Bierzynska A;Gangemi C;Lipska-Ziętkiewicz BS
Alport Variant Collaborative最近召开的Chandos House会议将Col4A5、Col4A3和Col4A4基因致病变异的筛查适应症从经典的Alport表型(血尿、肾功能衰竭、血尿或肾功能衰竭家族史)扩大到持续性蛋白尿、类固醇抵抗型肾病综合征、局灶性和节段性肾小球硬化(FSGS)、家族性IgA肾炎和无明显原因的终末期肾功能衰竭。会议完善了ACMG的Alport基因变异评估标准(Col4A3-5)。在IV型胶原α5、α3和α4链中发现了突变热点(PM1)，包括中间胶原区Gly-X-Y重复序列中的第1位甘氨酸残基和羧基非胶原区中的半胱氨酸残基(PP3)。它认为“成熟的”功能分析(PS3、BS3)仍然是主要的研究工具，但测序和微基因分析通常用于确认剪接变异体。由于Alport综合征不同的遗传方式，以及亚型变异(通常是非胶原中断附近的甘氨酸)和局部创始人效应的出现，无法定义微小等位基因频率(MAF)阈值，超过该阈值的变异被认为是良性的(BA1、BS1)。杂合的COL4A3和COL4A4变异是常见的“偶然”发现，也存在于正常的参考数据库中。对Col4A3-Col4A5基因亚型变异的识别和解释仍然是一个挑战。
The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3–5). It identified ‘mutational hotspots’ (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that ‘well-established’ functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common ‘incidental’ findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3–COL4A5 genes remains a challenge.
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影响因子：
3.6
作者：
Marini JC;Reich A;Smith SM
通讯作者：
Smith SM
影响因子：
3
作者：
Kashtan, Clifford E.;Ding, Jie;Gregory, Martin;Gross, Oliver;Heidet, Laurence;Knebelmann, Bertrand;Rheault, Michelle;Licht, Christoph
通讯作者：
Licht, Christoph
影响因子：
15.9
作者：
ANTIGNAC, C;KNEBELMANN, B;GUBLER, MC
通讯作者：
GUBLER, MC
影响因子：
19.6
作者：
通讯作者：
--
影响因子：
4
作者：
Mencarelli, Maria Antonietta;Heidet, Laurence;Renieri, Alessandra
通讯作者：
Renieri, Alessandra