Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes
Cardiomyopathy due to PRDM16 mutation: First description of a fetal presentation, with possible modifier genes
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DOI：
10.1002/ajmg.c.31766
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发表时间：
2020-01-22
影响因子：
3.1
通讯作者：
Kuentz, Paul
中科院分区：
文献类型：
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作者：
Delplancq, Geoffroy;Tarris, Georges;Kuentz, Paul
PRDM16（正调控结构域16）定位于染色体1p36缺失的患者中心肌病的关键区域，如Gajecka等人所定义，American Journal of Medical Genetics，2010，152 A，3074 - 3083中所述，并且编码锌指转录因子。我们提出了第一例胎儿左心室致密化不全（LVNC）与PRDM16变异。孕晚期的产科超音波检查发现一个羊水过多的胎儿，并有扩张的低动力心脏。妊娠终止后，胎儿病理学显示胎儿营养不良，伴有孤立性心脏肥大。内膜弹力纤维增生症与左心室心肌致密化不全有关。外显子组测序（ES）鉴定了一个从未报道的p. PRDM16中的（Gln353 *）杂合无义变体。根据美国医学遗传学和基因组学学会的指导方针，ES还在肌联蛋白基因（TTN）中鉴定出两种意义不明的罕见变异：一种从头错义p。（Lys14773Asn）变异和从母亲遗传的c.33043 + 5A> G变异。沿着PRDM 16新发可能致病性变体，TTN VOUS变体可能导致心脏表型的严重程度和早期发作。由于心肌病的遗传异质性，大面板甚至ES可以被认为是分子诊断的主要方法，特别是在胎儿介绍，其中多次命中似乎是常见的。
PRDM16 (positive regulatory domain 16) is localized in the critical region for cardiomyopathy in patients with deletions of chromosome 1p36, as defined by Gajecka et al., American Journal of Medical Genetics, 2010, 152A, 3074-3083, and encodes a zinc finger transcription factor. We present the first fetal case of left ventricular non-compaction (LVNC) with a PRDM16 variant. The third-trimester obstetric ultrasound revealed a hydropic fetus with hydramnios and expanded hypokinetic heart. After termination of pregnancy, foetopathology showed a eutrophic fetus with isolated cardiomegaly. Endocardial fibroelastosis was associated with non-compaction of the myocardium of the left ventricle. Exome sequencing (ES) identified a de novo unreported p.(Gln353*) heterozygous nonsense variant in PRDM16. ES also identified two rare variants of unknown significance, according to the American College of Medical Genetics and Genomics guidelines, in the titin gene (TTN): a de novo missense p.(Lys14773Asn) variant and a c.33043+5A>G variant inherited from the mother. Along with the PRDM16 de novo probably pathogenic variant, TTN VOUS variants could possibly contribute to the severity and early onset of the cardiac phenotype. Because of the genetic heterogeneity of cardiomyopathies, large panels or even ES could be considered as the main approaches for the molecular diagnosis, particularly in fetal presentations, where multiple hits seem to be common.