United Diagnostic and Research Center for Clinical Genetics, Women and Children's Hospital, School of Medicine and School of Public Health, Xiamen University, Xiamen, 361102, Fujian, China.
Department of Child Health, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China.
BMC Med Genomics. 2021 Mar 2;14(1):68. doi: 10.1186/s12920-021-00920-3.
KBG syndrome is a rare autosomal dominant genetic disease mainly caused by pathogenic variants of ankyrin repeat domain-containing protein 11 (ANKRD11) or deletions involving ANKRD11. Herein, we report a novel de novo heterozygous frameshift ANKRD11 variant via whole exome sequencing in a Chinese girl with KBG syndrome.
A 2-year-2-month-old girl presented with a short stature and developmental delay. Comprehensive physical examinations, endocrine laboratory tests and imaging examination were performed. Whole-exome sequencing and Sanger sequencing were used to detect and confirm the variant associated with KBG in this patient, respectively. The pathogenicity of the variant was further predicted by several in silico prediction tools. The patient was diagnosed as KBG syndrome with a short stature and developmental delay, as well as characteristic craniofacial abnormalities, including a triangular face, long philtrum, wide eyebrows, a broad nasal bridge, prominent and protruding ears, macrodontia of the upper central incisors, dental crowding, and binocular refractive error. Her skeletal anomalies included brachydactyly, fifth finger clinodactyly, and left-skewed caudal vertebrae. Electroencephalographic results generally showed normal background activity with sporadic spikes and slow wave complexes, as well as multiple spikes and slow wave complexes in the bilateral parietal, occipital, and posterior temporal regions during non-rapid-eye-movement sleep. Brain MRI showed a distended change in the bilateral ventricles and third ventricle, as well as malformation of the sixth ventricle. Whole exome sequencing revealed a novel heterozygous frameshift variant in the patient, ANKRD11 c.1366_1367dup, which was predicted to be pathogenic through in silico analysis. The patient had received physical therapy since 4 months of age, and improvement of gross motor dysfunction was evident.
The results of this study expand the spectrum of ANKRD11 variants in KBG patients and provide clinical phenotypic data for KBG syndrome at an early age. Our study also demonstrates that whole exome sequencing is an effective method for the diagnosis of rare genetic disorders.
KBG 综合征是一种罕见的常染色体显性遗传疾病，主要由锚蛋白重复域蛋白 11（ANKRD11）的致病性变异或涉及 ANKRD11 的缺失引起。在此，我们通过全外显子组测序报道了一名中国女孩 KBG 综合征的新型杂合性移码 ANKRD11 变异。
一名 2 岁 2 个月大的女孩因身材矮小和发育迟缓就诊。进行了全面的体格检查、内分泌实验室检查和影像学检查。分别通过全外显子组测序和 Sanger 测序来检测和确认与该患者 KBG 相关的变异。使用几种计算预测工具进一步预测了变异的致病性。该患者被诊断为 KBG 综合征，伴有身材矮小和发育迟缓，以及特征性颅面异常，包括三角脸、长人中、宽眉毛、宽鼻梁、突出和外耳突出、上颌中切牙的巨牙、牙列拥挤和双眼屈光不正。她的骨骼异常包括短指畸形、第五指弯曲和左侧尾椎骨偏斜。脑电图结果通常显示正常的背景活动，伴有散在的棘波和慢波复合波，以及双侧顶、枕、后颞区非快速眼动睡眠时的多发性棘波和慢波复合波。脑 MRI 显示双侧脑室和第三脑室扩张，第六脑室畸形。全外显子组测序显示患者存在 ANKRD11 c.1366_1367dup 杂合性移码变异，通过计算分析预测为致病性。该患者自 4 个月大开始接受物理治疗，粗大运动功能障碍改善明显。
本研究扩展了 KBG 患者中 ANKRD11 变异的谱，并为早期 KBG 综合征提供了临床表型数据。我们的研究还表明，全外显子组测序是诊断罕见遗传疾病的有效方法。
