PDF(Pubmed)
Abstract：
A genetic diagnosis of primary cardiomyopathies can be a long-unmet need in patients with complex phenotypes. We investigated a three-generation family with cardiomyopathy and various extracardiac abnormalities that had long sought a precise diagnosis. The 41-year-old proband had hypertrophic cardiomyopathy (HCM), left ventricular noncompaction, myocardial fibrosis, arrhythmias, and a short stature. His sister showed HCM, myocardial hypertrabeculation and fibrosis, sensorineural deafness, and congenital genitourinary malformations. Their father had left ventricular hypertrophy (LVH). The proband\'s eldest daughter demonstrated developmental delay and seizures. We performed a clinical examination and whole-exome sequencing for all available family members. All patients with HCM/LVH shared a c.4411-2A>C variant in ALPK3, a recently known HCM-causative gene. Functional studies confirmed that this variant alters ALPK3 canonical splicing. Due to extracardiac symptoms in the female patients, we continued the search and found two additional single-gene disorders. The proband\'s sister had a p.Trp329Gly missense in GATA3, linked to hypoparathyroidism, sensorineural deafness, and renal dysplasia; his daughter had a p.Ser251del in WDR45, associated with beta-propeller protein-associated neurodegeneration. This unique case of three monogenic disorders in one family shows how a comprehensive approach with thorough phenotyping and extensive genetic testing of all symptomatic individuals provides precise diagnoses and appropriate follow-up, embodying the concept of personalized medicine. We also present the first example of a splicing functional study for ALPK3 and describe the genotype-phenotype correlations in cardiomyopathy.
摘要：
在具有复杂表型的患者中，原发性心肌病的遗传诊断可能是长期未满足的需求。我们调查了一个患有心肌病和各种心外异常的三代家庭，这些家庭长期以来一直在寻求精确的诊断。41岁的先证者患有肥厚型心肌病（HCM），左心室不紧密,心肌纤维化，心律失常,身材矮小.他妹妹给HCM看了,心肌过度扩张和纤维化，感觉神经性耳聋,先天性泌尿生殖系统畸形.他们的父亲患有左心室肥厚（LVH）。先证者的长女表现出发育迟缓和癫痫发作。我们对所有可用的家庭成员进行了临床检查和全外显子组测序。所有HCM/LVH患者在ALPK3中共享c.4411-2A>C变体，这是一种最近已知的HCM致病基因。功能研究证实该变体改变了ALPK3规范剪接。由于女性患者的心外症状，我们继续搜索,发现另外两种单基因疾病.先证者的姐姐在GATA3中有p.Trp329Gly错义，与甲状旁腺功能减退症有关，感觉神经性耳聋,和肾脏发育不良；他的女儿在WDR45中患有p.Ser251del，与β-螺旋桨蛋白相关的神经变性有关。这种在一个家庭中出现三种单基因疾病的独特病例表明，全面的方法对所有有症状的个体进行全面的表型分析和广泛的基因检测如何提供精确的诊断和适当的随访，体现了个性化医疗的理念。我们还介绍了ALPK3剪接功能研究的第一个例子，并描述了心肌病的基因型-表型相关性。
