De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.
De Novo and Inherited Loss-of-Function Variants in TLK2: Clinical and Genotype-Phenotype Evaluation of a Distinct Neurodevelopmental Disorder.
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DOI：
10.1016/j.ajhg.2018.04.014
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发表时间：
2018-06-07
影响因子：
9.8
通讯作者：
Wilkie AOM
中科院分区：
文献类型：
--
作者：
Reijnders MRF;Miller KA;Alvi M;Goos JAC;Lees MM;de Burca A;Henderson A;Kraus A;Mikat B;de Vries BBA;Isidor B;Kerr B;Marcelis C;Schluth-Bolard C;Deshpande C;Ruivenkamp CAL;Wieczorek D;Deciphering Developmental Disorders Study;Baralle D;Blair EM;Engels H;Lüdecke HJ;Eason J;Santen GWE;Clayton-Smith J;Chandler K;Tatton-Brown K;Payne K;Helbig K;Radtke K;Nugent KM;Cremer K;Strom TM;Bird LM;Sinnema M;Bitner-Glindzicz M;van Dooren MF;Alders M;Koopmans M;Brick L;Kozenko M;Harline ML;Klaassens M;Steinraths M;Cooper NS;Edery P;Yap P;Terhal PA;van der Spek PJ;Lakeman P;Taylor RL;Littlejohn RO;Pfundt R;Mercimek-Andrews S;Stegmann APA;Kant SG;McLean S;Joss S;Swagemakers SMA;Douzgou S;Wall SA;Küry S;Calpena E;Koelling N;McGowan SJ;Twigg SRF;Mathijssen IMJ;Nellaker C;Brunner HG;Wilkie AOM
新一代测序是发现神经发育障碍 (NDD) 相关基因的强大工具。在此，我们报告利用全外显子组和全基因组测序技术、媒人数据库和国际合作，在 38 名无关个体和两名受影响的母亲中鉴定出一种由于乱七八糟样激酶 2 (TLK2) 的从头或遗传性杂合突变引起的独特综合征。受影响的个体具有一致的表型，其特征是轻度边缘性神经发育迟缓（86％）、行为障碍（68％）、严重胃肠道问题（63％）和面部畸形，包括睑裂（82％）、外眦（74％）、突出的鼻梁（68％）、宽鼻尖（66％）、上唇薄朱红色（62％）和上斜睑裂（55%）。对三名受影响个体的细胞系的分析表明，突变在至少两名病例受试者中通过功能丧失机制发挥作用。基因型-表型分析和计算模型面孔的比较表明，这些和其他具有功能丧失变异的个体的表型与具有其他变异类型（错义和C端截短）的个体的表型显着重叠。这表明 TLK2 的单倍体不足是最有可能的潜在疾病机制，导致一致的神经发育表型。这项工作通过鉴定来自 7 个不同国家 26 个不同中心的 40 名个体，说明了国际数据共享的力量，从而可以对由 TLK2 突变引起的独特 NDD 进行鉴定、临床描述和基因型-表型评估。
Next-generation sequencing is a powerful tool for the discovery of genes related to neurodevelopmental disorders (NDDs). Here, we report the identification of a distinct syndrome due to de novo or inherited heterozygous mutations in Tousled-like kinase 2 (TLK2) in 38 unrelated individuals and two affected mothers, using whole-exome and whole-genome sequencing technologies, matchmaker databases, and international collaborations. Affected individuals had a consistent phenotype, characterized by mild-borderline neurodevelopmental delay (86%), behavioral disorders (68%), severe gastro-intestinal problems (63%), and facial dysmorphism including blepharophimosis (82%), telecanthus (74%), prominent nasal bridge (68%), broad nasal tip (66%), thin vermilion of the upper lip (62%), and upslanting palpebral fissures (55%). Analysis of cell lines from three affected individuals showed that mutations act through a loss-of-function mechanism in at least two case subjects. Genotype-phenotype analysis and comparison of computationally modeled faces showed that phenotypes of these and other individuals with loss-of-function variants significantly overlapped with phenotypes of individuals with other variant types (missense and C-terminal truncating). This suggests that haploinsufficiency of TLK2 is the most likely underlying disease mechanism, leading to a consistent neurodevelopmental phenotype. This work illustrates the power of international data sharing, by the identification of 40 individuals from 26 different centers in 7 different countries, allowing the identification, clinical delineation, and genotype-phenotype evaluation of a distinct NDD caused by mutations in TLK2.
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DOI：
10.1016/j.mrgentox.2008.09.001
发表时间：
2008-11-17
影响因子：
1.9
作者：
Hashimoto, Mitsumasa;Matsui, Tadashi;Date, Takayasu
通讯作者：
Date, Takayasu
影响因子：
8
作者：
Li, Y;DeFatta, R;De Benedetti, A
通讯作者：
De Benedetti, A
影响因子：
10.5
作者：
Carrera, P;Moshkin, YM;Karch, F
通讯作者：
Karch, F
影响因子：
9.2
作者：
Silljé, HHW;Nigg, EA
通讯作者：
Nigg, EA
影响因子：
3.5
作者：
Yamakawa, A;Kameoka, Y;Date, T
通讯作者：
Date, T