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Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy.
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-07-15 , DOI: 10.1111/cge.13812 H K Robinson 1 , E Zaklyazminskaya 2, 3 , I Povolotskaya 3 , Y Surikova 2 , L Mallin 1 , C Armstrong 4 , D Mabin 5 , P J Benke 6, 7 , M R Chrisant 6 , M McDonald 8 , C C Marboe 9 , K E Agre 10 , D R Deyle 10 , K McWalter 11 , G Douglas 11 , M S Balashova 3, 12 , V Kaimonov 3 , N Shirokova 3 , E Pomerantseva 3 , C L Turner 13 , S Ellard 1, 14
Clinical Genetics ( IF 2.9 ) Pub Date : 2020-07-15 , DOI: 10.1111/cge.13812 H K Robinson 1 , E Zaklyazminskaya 2, 3 , I Povolotskaya 3 , Y Surikova 2 , L Mallin 1 , C Armstrong 4 , D Mabin 5 , P J Benke 6, 7 , M R Chrisant 6 , M McDonald 8 , C C Marboe 9 , K E Agre 10 , D R Deyle 10 , K McWalter 11 , G Douglas 11 , M S Balashova 3, 12 , V Kaimonov 3 , N Shirokova 3 , E Pomerantseva 3 , C L Turner 13 , S Ellard 1, 14
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Childhood dilated cardiomyopathy (DCM) is a leading cause of heart failure requiring cardiac transplantation and approximately 5% of cases result in sudden death. Knowledge of the underlying genetic cause can aid prognostication and clinical management and enables accurate recurrence risk counselling for the family. Here we used genomic sequencing to identify the causative genetic variant(s) in families with children affected by severe DCM. In an international collaborative effort facilitated by GeneMatcher, biallelic variants in PPP1R13L were identified in seven children with severe DCM from five unrelated families following exome or genome sequencing and inheritance‐based variant filtering. PPP1R13L encodes inhibitor of apoptosis‐stimulating protein of p53 protein (iASPP). In addition to roles in apoptosis, iASPP acts as a regulator of desmosomes and has been implicated in inflammatory pathways. DCM presented early (mean: 2 years 10 months; range: 3 months‐9 years) and was progressive, resulting in death (n = 3) or transplant (n = 3), with one child currently awaiting transplant. Genomic sequencing technologies are valuable for the identification of novel and emerging candidate genes. Biallelic variants in PPP1R13L were previously reported in a single consanguineous family with paediatric DCM. The identification here of a further five families now provides sufficient evidence to support a robust gene‐disease association between PPP1R13L and severe paediatric DCM. The PPP1R13L gene should be included in panel‐based genetic testing for paediatric DCM.
中文翻译：
PPP1R13L中的双等位基因变异会导致小儿扩张型心肌病。
儿童期扩张型心肌病（DCM）是心力衰竭的主要原因，需要进行心脏移植，约5％的病例导致猝死。了解潜在的遗传原因可以帮助进行预后和临床管理，并为家庭提供准确的复发风险咨询。在这里，我们使用基因组测序来鉴定患有严重DCM的儿童家庭中的致病性遗传变异。在GeneMatcher的推动下，一项国际合作努力通过对外显子组或基因组测序以及基于遗传的变体过滤，从五个无关家庭的7名患有严重DCM的儿童中鉴定出PPP1R13L的双等位基因变异。PPP1R13L编码p53蛋白（iASPP）的凋亡刺激蛋白抑制剂。除了在凋亡中发挥作用外，iASPP还充当桥粒的调节剂，并与炎症途径有关。DCM出现较早（平均：2年10个月；范围：3个月至9岁），并且进展缓慢，导致死亡（n = 3）或移植（n = 3），目前有一名儿童正在等待移植。基因组测序技术对于鉴定新型和新兴候选基因非常有价值。PPP1R13L中的双等位基因变体以前曾在一个小儿DCM的近亲家庭中报道过。现在在这里鉴定出的另外五个家族提供了充分的证据来支持PPP1R13L与严重儿科DCM之间的牢固的基因疾病关联。的PPP1R13L基因应纳入小儿DCM的基于面板的基因检测中。
更新日期：2020-09-23
中文翻译：
PPP1R13L中的双等位基因变异会导致小儿扩张型心肌病。
儿童期扩张型心肌病（DCM）是心力衰竭的主要原因，需要进行心脏移植，约5％的病例导致猝死。了解潜在的遗传原因可以帮助进行预后和临床管理，并为家庭提供准确的复发风险咨询。在这里，我们使用基因组测序来鉴定患有严重DCM的儿童家庭中的致病性遗传变异。在GeneMatcher的推动下，一项国际合作努力通过对外显子组或基因组测序以及基于遗传的变体过滤，从五个无关家庭的7名患有严重DCM的儿童中鉴定出PPP1R13L的双等位基因变异。PPP1R13L编码p53蛋白（iASPP）的凋亡刺激蛋白抑制剂。除了在凋亡中发挥作用外，iASPP还充当桥粒的调节剂，并与炎症途径有关。DCM出现较早（平均：2年10个月；范围：3个月至9岁），并且进展缓慢，导致死亡（n = 3）或移植（n = 3），目前有一名儿童正在等待移植。基因组测序技术对于鉴定新型和新兴候选基因非常有价值。PPP1R13L中的双等位基因变体以前曾在一个小儿DCM的近亲家庭中报道过。现在在这里鉴定出的另外五个家族提供了充分的证据来支持PPP1R13L与严重儿科DCM之间的牢固的基因疾病关联。的PPP1R13L基因应纳入小儿DCM的基于面板的基因检测中。
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