Schönberger J, Levy H, Grünig E, Sangwatanaroj S, Fatkin D, MacRae C, Stäcker H, Halpin C, Eavey R, Philbin E F, Katus H, Seidman J G, Seidman C E
Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA 02115, USA.
Circulation. 2000 Apr 18;101(15):1812-8. doi: 10.1161/01.cir.101.15.1812.
Dilated cardiomyopathy (DCM) and sensorineural hearing loss (SNHL) are prevalent disorders that occur alone or as components of complex multisystem syndromes. Multiple genetic loci have been identified that, when mutated, cause DCM or SNHL. However, the isolated coinheritance of these phenotypes has not been previously recognized.
Clinical evaluations of 2 kindreds demonstrated autosomal-dominant transmission and age-related penetrance of both SNHL and DCM in the absence of other disorders. Moderate-to-severe hearing loss was evident by late adolescence, whereas ventricular dysfunction produced progressive congestive heart failure after the fourth decade. DNA samples from the larger kindred (29 individuals) were used to perform a genome-wide linkage study. Polymorphic loci on chromosome 6q23 to 24 were coinherited with the disease (maximum logarithm of odds score, 4.88 at locus D6S2411). The disease locus must lie within a 2.8 cM interval between loci D6S975 and D6S292, a location that overlaps an SNHL disease locus (DFNA10). However, DFNA10 does not cause cardiomyopathy. The epicardin gene, which encodes a transcription factor expressed in the myocardium and cochlea, was assessed as a candidate gene by nucleotide sequence analysis; no mutations were identified.
A syndrome of juvenile-onset SNHL and adult-onset DCM is caused by a mutation at 6q23 to 24 (locus designated CMD1J). Recognition of this cardioauditory disorder allows for the identification of young adults at risk for serious heart disease, thereby enabling early intervention. Definition of the molecular cause of this syndrome may provide new information about important cell physiology common to both the ear and heart.
扩张型心肌病（DCM）和感音神经性听力损失（SNHL）是常见疾病，可单独发生或作为复杂多系统综合征的组成部分。已确定多个基因位点，这些位点发生突变时会导致DCM或SNHL。然而，此前尚未认识到这些表型的孤立共同遗传情况。
对两个家系的临床评估显示，在无其他疾病的情况下，SNHL和DCM均呈常染色体显性遗传及与年龄相关的外显率。青春期后期出现中度至重度听力损失，而心室功能障碍在40岁后导致进行性充血性心力衰竭。使用来自较大家系（29人）的DNA样本进行全基因组连锁研究。6号染色体q23至24上的多态性位点与疾病共同遗传（最大优势对数得分，在D6S2411位点为4.88）。疾病位点必定位于D6S975和D6S292位点之间2.8 cM的区间内，该位置与一个SNHL疾病位点（DFNA10）重叠。然而，DFNA10不会导致心肌病。通过核苷酸序列分析评估了编码在心肌和耳蜗中表达的转录因子的epicardin基因作为候选基因；未发现突变。
青少年期SNHL和成年期DCM综合征由6q23至24处的突变（位点命名为CMD1J）引起。认识到这种心脏听觉障碍有助于识别有严重心脏病风险的年轻人，从而实现早期干预。确定该综合征的分子病因可能会提供有关耳朵和心脏共有的重要细胞生理学的新信息。
