Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder

Author(s):
Elkhateeb, N.; Crookes, R.; Spiller, M.; Pavinato, L.; Palermo, F.; Brusco, A.; Parker, M.; Park, S.M.; Mendes, A.C.; Saraiva, J.M.; Nazaryan-Petersen, L.; Barakat, T.S.; Wilke, M.; Bhoj, E.; Ahrens-Nicklas, R.C.; Li, D.; Nomakuchi, T.; Brilstra, E.H.; Hunt, D.; Johnson, D.; Mansour, S.; Oprych, K.; Mehta, S.G.; Platzer, K.; Schnabel, F.; Kiep, H.; Faust, H.; Prinzing, G.; Wiltrout, K.; Radley, J.A.; Russi, A.H.S.; Atallah, I.; Campos-Xavier, B.; Amor, D.J.; Morgan, A.T.; Fagerberg, C.; Andersen, U.A.; Andersen, C.B.; Bijlsma, E.K.; Bird, L.M.; Mullegama, S.V.; Green, A.; Isidor, B.; Cogne, B.; Kenny, J.; Lynch, S.A.; Quin, S.; Low, K.; Herget, T.; Kortum, F.; Levy, R.J.; Morrison, J.L.; Wheeler, P.G.; Narumanch, T.; Peron, K.; Matthews, N.; Uhlman, J.; Bell, L.; Pang, L.W.; Scurr, I.; Belles, R.S.; Salbert, B.A.; Hammer, T.B.; Schaefer, G.B.; Green, S.; Ros, A.; Rodríguez-Palmero, A.; Visnjar, T.; Writzl, K.; Vasudevan, P.C.; Balasubramanian, M.
Published
2025
Publication type
Article / Letter to editor

Abstract

Purpose:The thousand and one kinase (TAOK) proteins are a group of serine/threonine-proteinkinases involved in signaling pathways, cytoskeleton regulation, and neuronal development.TAOK1variants are associated with a neurodevelopmental disorder (NDD) characterized b istinctive facial features, hypotonia, and feeding difficulties.TAOK2variants have beenreported to be associated with autism and early-onset obesity. However, a distinctTAOK2-NDD has not yet been delineated.

Methods:We retrospectively studied the clinical and genetic data of individuals recruited fromseveral centers withTAOK1andTAOK2variants that were detected through exome and genomesequencing.

Results:We report 50 individuals withTAOK1variants with associated phenotypes, includingneurodevelopmental abnormalities (100%), macrocephaly (83%), and hypotonia (58%). Wereport male genital anomalies and hypoglycemia as novel phenotypes. Thirty-seven uniqueTAOK1variants were identified. Most of the missense variants clustered in the protein kinasedomain at residues that are intolerant to missense variation. We report 10 patients withTAOK2variants with associated phenotypes, including neurodevelopmental abnormalities(100%), macrocephaly (75%), autism (75%), and obesity (70%). Conclusion:We describe the largest cohort ofTAOK1-NDD to date, to our knowledge,expanding its phenotype and genotype spectrum with 30 novel variants. We delineated thephenotype of a novelTAOK2-NDD associated with neurodevelopmental abnormalities, autism,macrocephaly, and obesity.

MAP3K enzymesNeurodevelopmental disorderTAOK1TAOK2Thousand and one kinase family
Date issued
2025-01-31
Language
English
Publisher
ELSEVIER SCIENCE INC
Is part of
Genetics in Medicine (2025), No. 3
hdl
1887/4293853
doi
10.1007/s10689-025-00512-5