Coughlin Curtis R, Swanson Michael A, Kronquist Kathryn, Acquaviva Cécile, Hutchin Tim, Rodríguez-Pombo Pilar, Väisänen Marja-Leena, Spector Elaine, Creadon-Swindell Geralyn, Brás-Goldberg Ana M, Rahikkala Elisa, Moilanen Jukka S, Mahieu Vincent, Matthijs Gert, Bravo-Alonso Irene, Pérez-Cerdá Celia, Ugarte Magdalena, Vianey-Saban Christine, Scharer Gunter H, Van Hove Johan L K
Section of Genetics, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Molecular Genetics Laboratory, Department of Pathology and Laboratory Medicine, Children's Hospital Colorado, Aurora, Colorado, USA.
Genet Med. 2017 Jan;19(1):104-111. doi: 10.1038/gim.2016.74. Epub 2016 Jun 30.
The study's purpose was to delineate the genetic mutations that cause classic nonketotic hyperglycinemia (NKH).
Genetic results, parental phase, ethnic origin, and gender data were collected from subjects suspected to have classic NKH. Mutations were compared with those in the existing literature and to the population frequency from the Exome Aggregation Consortium (ExAC) database.
In 578 families, genetic analyses identified 410 unique mutations, including 246 novel mutations. 80% of subjects had mutations in GLDC. Missense mutations were noted in 52% of all GLDC alleles, most private. Missense mutations were 1.5 times as likely to be pathogenic in the carboxy terminal of GLDC than in the amino-terminal part. Intragenic copy-number variations (CNVs) in GLDC were noted in 140 subjects, with biallelic CNVs present in 39 subjects. The position and frequency of the breakpoint for CNVs correlated with intron size and presence of Alu elements. Missense mutations, most often recurring, were the most common type of disease-causing mutation in AMT. Sequencing and CNV analysis identified biallelic pathogenic mutations in 98% of subjects. Based on genotype, 15% of subjects had an attenuated phenotype. The frequency of NKH is estimated at 1:76,000.
The 484 unique mutations now known in classic NKH provide a valuable overview for the development of genotype-based therapies.Genet Med 19 1, 104-111.
本研究旨在明确导致经典型非酮症高甘氨酸血症（NKH）的基因突变。
收集疑似患有经典型NKH患者的基因检测结果、亲本相位、种族来源和性别数据。将这些突变与现有文献中的突变以及外显子聚合联盟（ExAC）数据库中的人群频率进行比较。
在578个家庭中，基因分析确定了410个独特的突变，其中包括246个新突变。80%的患者在GLDC基因中存在突变。在所有GLDC等位基因中，52%存在错义突变，大多数为罕见突变。GLDC基因羧基末端的错义突变致病可能性是氨基末端的1.5倍。在140名受试者中发现了GLDC基因内的拷贝数变异（CNV），其中39名受试者存在双等位基因CNV。CNV断点的位置和频率与内含子大小及Alu元件的存在相关。错义突变是AMT基因中最常见的致病突变类型，且大多反复出现。测序和CNV分析在98%的受试者中确定了双等位基因致病突变。根据基因型，15%的受试者具有轻度表型。NKH的发病率估计为1:76,000。
目前已知的经典型NKH中的484个独特突变，为基于基因型的治疗方法的开发提供了有价值的概述。《基因医学》19 1, 104 - 111。
