Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder.
Elkhateeb N., Crookes R., Spiller M., Pavinato L., Palermo F., Brusco A., Parker M., Park S-M., Mendes AC., Saraiva JM., Hammer TB., Nazaryan-Petersen L., Barakat TS., Wilke M., Bhoj E., Ahrens-Nicklas RC., Li D., Nomakuchi T., Brilstra EH., Hunt D., Johnson D., Mansour S., Oprych K., Mehta SG., Platzer K., Schnabel F., Kiep H., Faust H., Prinzing G., Wiltrout K., Radley JA., Serrano Russi AH., Atallah I., Campos-Xavier B., Amor DJ., Morgan AT., Fagerberg C., Andersen UA., Andersen CB., Bijlsma EK., Bird LM., Mullegama SV., Green A., Isidor B., Cogné B., Kenny J., Lynch SA., Quin S., Low K., Herget T., Kortüm F., Levy RJ., Morrison JL., Wheeler PG., Narumanch T., Peron K., Matthews N., Uhlman J., Bell L., Pang L., Scurr I., Belles RS., Salbert BA., Schaefer GB., Green S., Ros A., Rodríguez-Palmero A., Višnjar T., Writzl K., Vasudevan PC., Balasubramanian M.
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 patients 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.