扩展TAOK1神经发育障碍的表型和基因型谱并明确TAOK2神经发育障碍。
Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.
作者信息
Elkhateeb Nour, Crookes Renarta, Spiller Michael, Pavinato Lisa, Palermo Flavia, Brusco Alfredo, Parker Michael, Park Soo-Mi, Mendes Ariana Costa, Saraiva Jorge M, Hammer Trine Bjørg, Nazaryan-Petersen Lusine, Barakat Tahsin Stefan, Wilke Martina, Bhoj Elizabeth, Ahrens-Nicklas Rebecca C, Li Dong, Nomakuchi Tomoki, Brilstra Eva H, Hunt David, Johnson Diana, Mansour Sahar, Oprych Kathryn, Mehta Sarju G, Platzer Konrad, Schnabel Franziska, Kiep Henriette, Faust Helene, Prinzing Gillian, Wiltrout Kimberly, Radley Jessica A, Serrano Russi Alvaro H, Atallah Isis, Campos-Xavier Belinda, Amor David J, Morgan Angela T, Fagerberg Christina, Andersen Ulla A, Andersen Charlotte B, Bijlsma Emilia K, Bird Lynne M, Mullegama Sureni V, Green Andrew, Isidor Bertrand, Cogné Benjamin, Kenny Janna, Lynch Sally A, Quin Shauna, Low Karen, Herget Theresia, Kortüm Fanny, Levy Rebecca J, Morrison Jennifer L, Wheeler Patricia G, Narumanch TaraChandra, Peron Kristina, Matthews Nicole, Uhlman Jillian, Bell Lauren, Pang Lewis, Scurr Ingrid, Belles Rebecca S, Salbert Bonnie Anne, Schaefer Gerald Bradley, Green Sarah, Ros Andrea, Rodríguez-Palmero Agustí, Višnjar Tanja, Writzl Karin, Vasudevan Pradeep C, Balasubramanian Meena
机构信息
Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
Sheffield Diagnostic Genetics Service, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, United Kingdom.
出版信息
Genet Med. 2025 Mar;27(3):101348. doi: 10.1016/j.gim.2024.101348. Epub 2024 Dec 27.
PURPOSE
The thousand and one kinase (TAOK) proteins are a group of serine/threonine-protein kinases involved in signaling pathways, cytoskeleton regulation, and neuronal development. TAOK1 variants are associated with a neurodevelopmental disorder (NDD) characterized by distinctive facial features, hypotonia, and feeding difficulties. TAOK2 variants have been reported to be associated with autism and early-onset obesity. However, a distinct TAOK2-NDD has not yet been delineated.
METHODS
We retrospectively studied the clinical and genetic data of individuals recruited from several centers with TAOK1 and TAOK2 variants that were detected through exome and genome sequencing.
RESULTS
We report 50 individuals with TAOK1 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). We report male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven unique TAOK1 variants were identified. Most of the missense variants clustered in the protein kinase domain at residues that are intolerant to missense variation. We report 10 individuals with TAOK2 variants with associated phenotypes, including neurodevelopmental abnormalities (100%), macrocephaly (75%), autism (75%), and obesity (70%).
CONCLUSION
We describe the largest cohort of TAOK1-NDD to date, to our knowledge, expanding its phenotype and genotype spectrum with 30 novel variants. We delineated the phenotype of a novel TAOK2-NDD associated with neurodevelopmental abnormalities, autism, macrocephaly, and obesity.
目的
千一激酶（TAOK）蛋白是一组丝氨酸/苏氨酸蛋白激酶，参与信号通路、细胞骨架调节和神经元发育。TAOK1变异与一种神经发育障碍（NDD）相关，其特征为独特的面部特征、肌张力减退和喂养困难。据报道，TAOK2变异与自闭症和早发性肥胖有关。然而，一种独特的TAOK2-NDD尚未被明确界定。
方法
我们回顾性研究了从多个中心招募的携带通过外显子组和基因组测序检测到的TAOK1和TAOK2变异的个体的临床和遗传数据。
结果
我们报告了50例携带TAOK1变异及相关表型的个体，包括神经发育异常（100%）、巨头畸形（83%）和肌张力减退（58%）。我们报告男性生殖器异常和低血糖为新的表型。鉴定出37种独特的TAOK1变异。大多数错义变异聚集在蛋白激酶结构域中对错过变异不耐受的残基处。我们报告了10例携带TAOK2变异及相关表型的个体，包括神经发育异常（100%）、巨头畸形（75%）、自闭症（75%）和肥胖（70%）。
结论
据我们所知，我们描述了迄今为止最大的TAOK1-NDD队列，用30种新变异扩展了其表型和基因型谱。我们明确了一种与神经发育异常、自闭症、巨头畸形和肥胖相关的新型TAOK2-NDD的表型。
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