Chang Yuchen, Wacker Julie, Ingles Jodie, Macciocca Ivan, King Ingrid, Semsarian Christopher, McGaughran Julie, Weintraub Robert G, Bagnall Richard D
Bioinformatics and Molecular Genetics at Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia.
Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
J Med Genet. 2024 Jan 19;61(2):171-175. doi: 10.1136/jmg-2023-109455.
encodes a cardiac transcription factor that is associated with atrial septal defects. Recent studies implicate loss-of-function variants with left ventricular non-compaction cardiomyopathy (LVNC), although clinical and genetic data in families are limited. We report four families with loss-of-function variants that segregate with LVNC. Genetic testing using genome or exome sequencing was performed in index cases, variants were validated with Sanger sequencing, and cascade genetic testing was performed in family members. A multi-exon deletion, small deletion, essential splice site variant and nonsense variant in were found in four families. The index cases in two families were symptomatic children with identical congenital heart diseases and LVNC who developed different cardiomyopathy phenotypes with one developing heart failure requiring transplantation. In another family, the child index case had LVNC and congestive heart failure requiring heart transplantation. In the fourth family, the index case was a symptomatic adult with LVNC. In all families, the variants segregated in relatives with isolated LVNC, or with congenital heart disease or cardiomyopathy. Family members displayed a clinical spectrum from asymptomatic to severe presentations including heart failure. Our data strengthen loss-of-function variants as a rare cause of LVNC and support inclusion in genetic testing of LVNC.
编码一种与房间隔缺损相关的心脏转录因子。最近的研究表明功能丧失变异与左心室致密化不全心肌病（LVNC）有关，尽管家族中的临床和遗传数据有限。我们报告了四个携带与LVNC共分离的功能丧失变异的家族。对先证者进行了使用基因组或外显子组测序的基因检测，变异通过桑格测序进行验证，并对家庭成员进行了级联基因检测。在四个家族中发现了一个多外显子缺失、小缺失、关键剪接位点变异和无义变异。两个家族中的先证者是有相同先天性心脏病和LVNC的有症状儿童，他们发展出不同的心肌病表型，其中一个发展为需要移植的心力衰竭。在另一个家族中，儿童先证者患有LVNC和需要心脏移植的充血性心力衰竭。在第四个家族中，先证者是一名有症状的患有LVNC的成年人。在所有家族中，变异在患有孤立性LVNC、或先天性心脏病或心肌病的亲属中分离。家庭成员表现出从无症状到包括心力衰竭在内的严重表现的临床谱。我们的数据强化了功能丧失变异是LVNC的罕见病因这一观点，并支持将其纳入LVNC的基因检测中。
