Long Pamela A, Evans Jared M, Olson Timothy M
Mayo Graduate School, Molecular Pharmacology and Experimental Therapeutics Track, Mayo Clinic, Rochester, Minnesota; Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, Minnesota.
Am J Med Genet A. 2015 Apr;167A(4):886-90. doi: 10.1002/ajmg.a.36994. Epub 2015 Feb 23.
Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care.
特发性扩张型心肌病是一种遗传性、基因异质性疾病，其特征为进行性心力衰竭。扩张型心肌病通常表现为常染色体显性遗传，但在成年之前常无明显临床症状。我们试图在一名患有严重心力衰竭的1个月大男性患儿中探寻特发性、非综合征性扩张型心肌病的分子基础。此前对血液、尿液和皮肤活检标本进行的全面检测未发现代谢、线粒体、贮积和感染性病因。眼科检查正常。染色体微阵列和商用扩张型心肌病基因检测未能识别出致病突变。父母的筛查超声心动图未显示临床隐匿性扩张型心肌病的证据。基于研究目的，对该三口之家进行了全外显子组测序，筛选罕见、有害、隐性和新生遗传变异。在ALMS1基因中发现了致病的复合杂合性截短突变，确诊为阿尔斯特伦综合征，并促使披露基因检测结果。阿尔斯特伦综合征是儿童扩张型心肌病的已知病因，但由于其罕见性和多系统临床表现的年龄依赖性出现，诊断往往延迟且容易误诊。患儿6个月大时最终出现了双侧眼球震颤和远视，这是该综合征的特征性表现。早期诊断有助于指导对其他器官系统进行临床监测，并进行症状前干预。此外，认识到隐性遗传是散发性疾病的发病机制，也为计划生育提供了依据。本病例凸显了小儿扩张型心肌病标准基因检测的局限性，并例证了全外显子组测序在解决诊断难题和实现个性化医疗方面所具有的潜力。
