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

Nour Elkhateeb; Renarta Crookes; Michael Spiller; Lisa Pavinato; Flavia Palermo; Alfredo Brusco; Michael Parker; Soo-Mi Park; Ariana Costa Mendes; Jorge M Saraiva; Trine Bjørg Hammer; Lusine Nazaryan-Petersen; Tahsin Stefan Barakat; Martina Wilke; Elizabeth Bhoj; Rebecca C Ahrens-Nicklas; Dong Li; Tomoki Nomakuchi; Eva H Brilstra; David Hunt; Diana Johnson; Sahar Mansour; Kathryn Oprych; Sarju G Mehta; Konrad Platzer; Franziska Schnabel; Henriette Kiep; Helene Faust; Gillian Prinzing; Kimberly Wiltrout; Jessica A Radley; Alvaro H Serrano Russi; Isis Atallah; Belinda Campos-Xavier; David J Amor; Angela T Morgan; Christina Fagerberg; Ulla A Andersen; Charlotte Brasch-Andersen; Emilia K Bijlsma; Lynne M Bird; Sureni V Mullegama; Andrew Green; Bertrand Isidor; Benjamin Cogné; Janna Kenny; Sally A Lynch; Shauna Quin; Karen Low; Theresia Herget; Fanny Kortüm; Rebecca J Levy; Jennifer L Morrison; Patricia G Wheeler; TaraChandra Narumanch; Kristina Peron; Nicole Matthews; Jillian Uhlman; Lauren Bell; Lewis Pang; Ingrid Scurr; Rebecca S Belles; Bonnie Anne Salbert; Gerald Bradley Schaefer; Sarah Green; Andrea Ros; Agustí Rodríguez-Palmero; Tanja Višnjar; Karin Writzl; Pradeep C Vasudevan; Meena Balasubramanian

doi:10.1016/j.gim.2024.101348

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

Nour Elkhateeb, Renarta Crookes, Michael Spiller, Lisa Pavinato, Flavia Palermo, Alfredo Brusco, Michael Parker, Soo-Mi Park, Ariana Costa Mendes, Jorge M Saraiva, Trine Bjørg Hammer, Lusine Nazaryan-Petersen, Tahsin Stefan Barakat, Martina Wilke, Elizabeth Bhoj, Rebecca C Ahrens-Nicklas, Dong Li, Tomoki Nomakuchi, Eva H Brilstra, David HuntDiana Johnson, Sahar Mansour, Kathryn Oprych, Sarju G Mehta, Konrad Platzer, Franziska Schnabel, Henriette Kiep, Helene Faust, Gillian Prinzing, Kimberly Wiltrout, Jessica A Radley, Alvaro H Serrano Russi, Isis Atallah, Belinda Campos-Xavier, David J Amor, Angela T Morgan, Christina Fagerberg, Ulla A Andersen, Charlotte Brasch-Andersen, Emilia K Bijlsma, Lynne M Bird, Sureni V Mullegama, Andrew Green, Bertrand Isidor, Benjamin Cogné, Janna Kenny, Sally A Lynch, Shauna Quin, Karen Low, Theresia Herget, Fanny Kortüm, Rebecca J Levy, Jennifer L Morrison, Patricia G Wheeler, TaraChandra Narumanch, Kristina Peron, Nicole Matthews, Jillian Uhlman, Lauren Bell, Lewis Pang, Ingrid Scurr, Rebecca S Belles, Bonnie Anne Salbert, Gerald Bradley Schaefer, Sarah Green, Andrea Ros, Agustí Rodríguez-Palmero, Tanja Višnjar, Karin Writzl, Pradeep C Vasudevan, Meena Balasubramanian^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

Abstract

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.

Original language	English
Article number	101348
Journal	Genetics in Medicine
Volume	27
Issue number	3
Number of pages	17
ISSN	1098-3600
DOIs	https://doi.org/10.1016/j.gim.2024.101348
Publication status	Published - Mar 2025

Bibliographical note

Keywords

Adolescent
Adult
Autistic Disorder/genetics
Child
Child, Preschool
Exome Sequencing
Female
Genotype
Humans
Infant
Male
Megalencephaly/genetics
Muscle Hypotonia/genetics
Mutation, Missense/genetics
Neurodevelopmental Disorders/genetics
Obesity/genetics
Phenotype
Protein Serine-Threonine Kinases/genetics
Retrospective Studies

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10.1016/j.gim.2024.101348Licence: CC BY

Cite this

Elkhateeb, N., Crookes, R., Spiller, M., Pavinato, L., Palermo, F., Brusco, A., Parker, M., Park, S.-M., Mendes, A. C., Saraiva, J. M., Hammer, T. B., Nazaryan-Petersen, L., Barakat, T. S., Wilke, M., Bhoj, E., Ahrens-Nicklas, R. C., Li, D., Nomakuchi, T., Brilstra, E. H., ... Balasubramanian, M. (2025). Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder. Genetics in Medicine, 27(3), Article 101348. https://doi.org/10.1016/j.gim.2024.101348

@article{7cfa73dda5874117ba0feffaa631524d,

title = "Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder",

abstract = "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.",

keywords = "Adolescent, Adult, Autistic Disorder/genetics, Child, Child, Preschool, Exome Sequencing, Female, Genotype, Humans, Infant, Male, Megalencephaly/genetics, Muscle Hypotonia/genetics, Mutation, Missense/genetics, Neurodevelopmental Disorders/genetics, Obesity/genetics, Phenotype, Protein Serine-Threonine Kinases/genetics, Retrospective Studies",

author = "Nour Elkhateeb and Renarta Crookes and Michael Spiller and Lisa Pavinato and Flavia Palermo and Alfredo Brusco and Michael Parker and Soo-Mi Park and Mendes, {Ariana Costa} and Saraiva, {Jorge M} and Hammer, {Trine Bj{\o}rg} and Lusine Nazaryan-Petersen and Barakat, {Tahsin Stefan} and Martina Wilke and Elizabeth Bhoj and Ahrens-Nicklas, {Rebecca C} and Dong Li and Tomoki Nomakuchi and Brilstra, {Eva H} and David Hunt and Diana Johnson and Sahar Mansour and Kathryn Oprych and Mehta, {Sarju G} and Konrad Platzer and Franziska Schnabel and Henriette Kiep and Helene Faust and Gillian Prinzing and Kimberly Wiltrout and Radley, {Jessica A} and {Serrano Russi}, {Alvaro H} and Isis Atallah and Belinda Campos-Xavier and Amor, {David J} and Morgan, {Angela T} and Christina Fagerberg and Andersen, {Ulla A} and Charlotte Brasch-Andersen and Bijlsma, {Emilia K} and Bird, {Lynne M} and Mullegama, {Sureni V} and Andrew Green and Bertrand Isidor and Benjamin Cogn{\'e} and Janna Kenny and Lynch, {Sally A} and Shauna Quin and Karen Low and Theresia Herget and Fanny Kort{\"u}m and Levy, {Rebecca J} and Morrison, {Jennifer L} and Wheeler, {Patricia G} and TaraChandra Narumanch and Kristina Peron and Nicole Matthews and Jillian Uhlman and Lauren Bell and Lewis Pang and Ingrid Scurr and Belles, {Rebecca S} and Salbert, {Bonnie Anne} and Schaefer, {Gerald Bradley} and Sarah Green and Andrea Ros and Agust{\'i} Rodr{\'i}guez-Palmero and Tanja Vi{\v s}njar and Karin Writzl and Vasudevan, {Pradeep C} and Meena Balasubramanian",

year = "2025",

month = mar,

doi = "10.1016/j.gim.2024.101348",

language = "English",

volume = "27",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Elsevier",

number = "3",

}

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 , Brasch-Andersen, C, 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 2025, 'Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder', Genetics in Medicine, vol. 27, no. 3, 101348. https://doi.org/10.1016/j.gim.2024.101348

TY - JOUR

T1 - Expanding the phenotype and genotype spectrum of TAOK1 neurodevelopmental disorder and delineating TAOK2 neurodevelopmental disorder

AU - Elkhateeb, Nour

AU - Crookes, Renarta

AU - Spiller, Michael

AU - Pavinato, Lisa

AU - Palermo, Flavia

AU - Brusco, Alfredo

AU - Parker, Michael

AU - Park, Soo-Mi

AU - Mendes, Ariana Costa

AU - Saraiva, Jorge M

AU - Hammer, Trine Bjørg

AU - Nazaryan-Petersen, Lusine

AU - Barakat, Tahsin Stefan

AU - Wilke, Martina

AU - Bhoj, Elizabeth

AU - Ahrens-Nicklas, Rebecca C

AU - Li, Dong

AU - Nomakuchi, Tomoki

AU - Brilstra, Eva H

AU - Hunt, David

AU - Johnson, Diana

AU - Mansour, Sahar

AU - Oprych, Kathryn

AU - Mehta, Sarju G

AU - Platzer, Konrad

AU - Schnabel, Franziska

AU - Kiep, Henriette

AU - Faust, Helene

AU - Prinzing, Gillian

AU - Wiltrout, Kimberly

AU - Radley, Jessica A

AU - Serrano Russi, Alvaro H

AU - Atallah, Isis

AU - Campos-Xavier, Belinda

AU - Amor, David J

AU - Morgan, Angela T

AU - Fagerberg, Christina

AU - Andersen, Ulla A

AU - Brasch-Andersen, Charlotte

AU - Bijlsma, Emilia K

AU - Bird, Lynne M

AU - Mullegama, Sureni V

AU - Green, Andrew

AU - Isidor, Bertrand

AU - Cogné, Benjamin

AU - Kenny, Janna

AU - Lynch, Sally A

AU - Quin, Shauna

AU - Low, Karen

AU - Herget, Theresia

AU - Kortüm, Fanny

AU - Levy, Rebecca J

AU - Morrison, Jennifer L

AU - Wheeler, Patricia G

AU - Narumanch, TaraChandra

AU - Peron, Kristina

AU - Matthews, Nicole

AU - Uhlman, Jillian

AU - Bell, Lauren

AU - Pang, Lewis

AU - Scurr, Ingrid

AU - Belles, Rebecca S

AU - Salbert, Bonnie Anne

AU - Schaefer, Gerald Bradley

AU - Green, Sarah

AU - Ros, Andrea

AU - Rodríguez-Palmero, Agustí

AU - Višnjar, Tanja

AU - Writzl, Karin

AU - Vasudevan, Pradeep C

AU - Balasubramanian, Meena

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - Adolescent

KW - Adult

KW - Autistic Disorder/genetics

KW - Child

KW - Child, Preschool

KW - Exome Sequencing

KW - Female

KW - Genotype

KW - Humans

KW - Infant

KW - Male

KW - Megalencephaly/genetics

KW - Muscle Hypotonia/genetics

KW - Mutation, Missense/genetics

KW - Neurodevelopmental Disorders/genetics

KW - Obesity/genetics

KW - Phenotype

KW - Protein Serine-Threonine Kinases/genetics

KW - Retrospective Studies

U2 - 10.1016/j.gim.2024.101348

DO - 10.1016/j.gim.2024.101348

M3 - Journal article

C2 - 39737487

SN - 1098-3600

VL - 27

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 3

M1 - 101348

ER -

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

Abstract

Bibliographical note

Keywords

Documents & Links

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Cite this