Mai J H, Ou Z H, Chen L, Duan J, Liao J X, Han C X
Department of Neurology, Shenzhen Children's Hospital, Shenzhen 58038, China.
Department of Cardiology, Shenzhen Children's Hospital, Shenzhen 518038, China.
Zhonghua Er Ke Za Zhi. 2020 Oct 2;58(10):833-837. doi: 10.3760/cma.j.cn112140-20200421-00411.
To explore the clinical characteristics of intellectual developmental disorder with cardiac arrhythmia syndrome (IDDCA) in a family caused by GNB5 gene variation and to review the literature. The clinical and genetic data of an infant with IDDCA, who visited Shenzhen Children's Hospital in September 2018, were collected and analyzed. His parents' and brother's gene analysis was also done by the next-generation sequencing and confirmed by Sanger sequencing. Related literature up to March 2020 was searched in Online Mendelian Inheritance in Man (OMIM), PubMed, CNKI and Wanfang databases with "GNB5" "IDDCA" "LADCI" "intellectual developmental disorder with cardial arrhythmia" "language delay and attention deficit-hyperactivity disorder or cognitive impairment with or without cardiac arrhythmia" as the key words. The related papers were retrieved and analyzed to summarize the clinical and genetic characteristics of this disorder. The proband was an 11-month-old boy who presented with mental and motor developmental retardation, accompanied with convulsion and muscle weakness. Sinus arrest was also detected. His electroencephalogram (EEG) and flash visual evoked potential (FVEP) were both abnormal. Genetic analysis identified the homozygous frameshift variation of GNB5 gene (c.136delG, p.Glu46Argfs*8) in this infant and heterozygous variation in his parents, confirmed the diagnosis of IDDCA. The same GNB5 variation was identified in his brother, who was 4 years and 8 months old and had developed the similar clinical manifestations after birth. There were only 7 papers reporting this disease in the literature review, with a total of 27 patients from 14 families. Including these 2 cases, there were 29 patients in total, whose age of diagnosis ranged from 5.5 months to 23 years. Among all the patients, 20 cases (69%) were diagnosed as IDDCA, while 8 cases (28%) as LADCI; and 11 (38%) were males while 18 (62%) females. Regarding the clinical features, 66% (19/29) had mental retardation, 41% (12/29) had seizures, 79% (23/29) developed language delay and 62%（18/29） had sinus node dysfunction. Genetic tests showed that 4 patients from 3 families had complex heterozygous variation, and 25 patients (86%) from 12 families had homozygous variation. Seventeen patients from 8 families were consanguineous. Among the total 12 variations, there were 4 nonsense, 3 frameshift, 2 missense and 2 shear mutations, and 1 shear disorder caused by synonymous mutation. IDDCA caused by GNB5 gene variations mainly manifests as general developmental delay or severe mental retardation, and sinus node dysfunction. GNB5 associated syndromes have phenotypic heterogeneity and are inherited in an autosomal recessive manner.
探讨由GNB5基因变异引起的一家系智力发育障碍合并心律失常综合征（IDDCA）的临床特征并进行文献复习。收集并分析2018年9月就诊于深圳市儿童医院的1例IDDCA患儿的临床及遗传学资料，采用二代测序技术对其父母及哥哥进行基因分析，并通过Sanger测序进行验证。以“GNB5”“IDDCA”“LADCI”“智力发育障碍合并心律失常”“语言发育迟缓伴注意力缺陷多动障碍或有或无心律失常的认知障碍”为关键词，检索截至2020年3月的在线人类孟德尔遗传数据库（OMIM）、PubMed、中国知网（CNKI）及万方数据库中的相关文献，对检索到的文献进行分析，总结该疾病的临床及遗传学特征。先证者为11月龄男童，表现为精神运动发育迟缓，伴有惊厥及肌无力，同时检测到窦性停搏，脑电图（EEG）及闪光视觉诱发电位（FVEP）均异常。基因分析确定该患儿存在GNB5基因纯合移码变异（c.136delG，p.Glu46Argfs*8），其父母为杂合变异，确诊为IDDCA。在其4岁8个月的哥哥中也检测到相同的GNB5变异，出生后已出现相似临床表现。文献复习仅7篇报道该病，共涉及14个家系27例患者，包括本2例在内共29例患者，诊断年龄5.5个月至23岁。所有患者中，20例（69%）诊断为IDDCA，8例（28%）为LADDCI；男性11例（38%），女性18例（62%）。临床特征方面，66%（19/29）有智力发育迟缓，41%（12/29）有惊厥发作，79%（23/29）有语言发育迟缓，62%（18/29）有窦房结功能障碍。基因检测显示，3个家系的4例患者为复合杂合变异，12个家系的25例患者（86%）为纯合变异。8个家系的17例患者为近亲婚配。12种变异中，4种为无义变异，3种为移码变异，2种为错义变异，2种为剪切突变，1种同义突变导致剪切异常。GNB5基因变异所致IDDCA主要表现为全面发育迟缓或重度智力发育障碍及窦房结功能障碍。GNB5相关综合征具有表型异质性，呈常染色体隐性遗传。
