Huang Yanru, Mei Libin, Wang Yangdan, Ye Huiming, Ma Xiaomin, Zhang Jian, Cai Meijiao, Li Ping, Ge Yunsheng, Zhou Yulin
Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, China.
United Diagnostic and Research Center for Clinical Genetics, School of Public Health, Xiamen University, Xiamen, China.
Front Genet. 2021 Jul 22;12:676832. doi: 10.3389/fgene.2021.676832. eCollection 2021.
Global developmental delay has markedly high phenotypic and genetic heterogeneity, and is a great challenge for clinical diagnosis. Hypotonia, ataxia, and delayed development syndrome (HADDS), first reported in 2017, is one type of global development delay. The aim of the present study was to investigate the genetic etiology of a Chinese boy with global developmental delay.
We combined clinical and imaging phenotyping with trio whole-exome sequencing and Sanger sequencing to the patient and his clinically unaffected parents. A luciferase reporter and immunofluorescence were performed to detect the effect of mutation on transcriptional activity and subcellular localization.
The patient presented with several previously unreported symptoms in the patients with HADDS, including hemangiomas, mild hearing abnormalities and tracheomalacia. A novel c.589A > G missense mutation (p.Asn197Asp, p.N197D) was identified in the patient but not in his parents. By constructing the plasmid and transfecting HEK293T cells, -N197D mutant showed impaired activation of luciferase reporter expression of the p21 promoter, and the mutant affected its entry into the nucleus.
To the best of our knowledge, this is the first report of pathogenic mutation which associated with HADDS in the Chinese population. Our results expand the phenotypes and pathogenic mutation spectrum of HADDS, thus potentially facilitating the clinical diagnosis and genetic counseling of HADDS patients.
全球发育迟缓具有显著的高表型和遗传异质性，对临床诊断构成巨大挑战。肌张力减退、共济失调和发育迟缓综合征（HADDS）于2017年首次报道，是全球发育迟缓的一种类型。本研究的目的是调查一名患有全球发育迟缓的中国男孩的遗传病因。
我们将临床和影像学表型分析与三联体全外显子测序以及对患者及其临床未受影响的父母进行桑格测序相结合。进行荧光素酶报告基因检测和免疫荧光检测，以检测突变对转录活性和亚细胞定位的影响。
该患者出现了一些HADDS患者中先前未报道的症状，包括血管瘤、轻度听力异常和气管软化。在患者中鉴定出一种新的c.589A>G错义突变（p.Asn197Asp，p.N197D），但其父母未检测到。通过构建质粒并转染HEK293T细胞，-N197D突变体显示p21启动子的荧光素酶报告基因表达激活受损，并且该突变体影响其进入细胞核。
据我们所知，这是中国人群中与HADDS相关的致病突变的首次报道。我们的结果扩展了HADDS的表型和致病突变谱，从而可能有助于HADDS患者的临床诊断和遗传咨询。
