title: Mutations in TBCK, Encoding TBC1-Domain-Containing Kinase, Lead to a Recognizable Syndrome of Intellectual Disability and Hypotonia.
abstract: Through an international multi-center collaboration, 13 individuals from nine unrelated families and affected by likely pathogenic biallelic variants in TBC1-domain-containing kinase (TBCK) were identified through whole-exome sequencing. All affected individuals were found to share a core phenotype of intellectual disability and hypotonia, and many had seizures and showed brain atrophy and white-matter changes on neuroimaging. Minor non-specific facial dysmorphism was also noted in some individuals, including multiple older children who developed coarse features similar to those of storage disorders. TBCK has been shown to regulate the mammalian target of rapamycin (mTOR) signaling pathway, which is also stimulated by exogenous leucine supplementation. TBCK was absent in cells from affected individuals, and decreased phosphorylation of phospho-ribosomal protein S6 was also observed, a finding suggestive of downregulation of mTOR signaling. Lastly, we demonstrated that activation of the mTOR pathway in response to L-leucine supplementation was retained, suggesting a possible avenue for directed therapies for this condition.
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. Electronic address: bhoje@email.chop.edu.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Bhoj
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Harr
authors.affiliation: Pediatric Neurology Unit, Hadassah University Hospital, Mount Scopus, Jerusalem 91120, Israel; Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Shimon
authors.initials: S
authors.lastname: Edvardson
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Chisholm
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Juusola
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Ganka
authors.initials: G
authors.lastname: Douglas
authors.affiliation: GeneDx, Gaithersburg, MD 20877, USA.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Guillen Sacoto
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Necker-Enfants Malades Hospital, 75015 Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Siquier-Pernet
authors.affiliation: Département de Neurologie, Etablissement Hospitalier Spécialisé de Benaknoun, Algers, Algeria.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Saadi
authors.affiliation: Genomic Platform, INSERM UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Bole-Feysot
authors.affiliation: Plateforme de Bioinformatique, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, 75015 Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Nitschke
authors.affiliation: Emory Genetics Laboratory, Emory University, Decatur, GA 30033, USA.
authors.forename: Alekhya
authors.initials: A
authors.lastname: Narravula
authors.affiliation: Nicklaus Children's Hospital, Miami, FL, 33155, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Walke
authors.affiliation: Department of Medical Genetics & Genomic Medicine, St. Peter's University Hospital, New Brunswick, NJ 08901, USA.
authors.forename: Michele B
authors.initials: MB
authors.lastname: Horner
authors.affiliation: Department of Medical Genetics & Genomic Medicine, St. Peter's University Hospital, New Brunswick, NJ 08901, USA.
authors.forename: Debra-Lynn
authors.initials: DL
authors.lastname: Day-Salvatore
authors.affiliation: Nicklaus Children's Hospital, Miami, FL, 33155, USA.
authors.forename: Parul
authors.initials: P
authors.lastname: Jayakar
authors.affiliation: Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA 23507, USA.
authors.forename: Samantha A Schrier
authors.initials: SA
authors.lastname: Vergano
authors.affiliation: Department of Pediatrics, McMaster University Medical Center, Hamilton, ON L8N 3Z5, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.affiliation: Emory Genetics Laboratory, Emory University, Decatur, GA 30033, USA.
authors.forename: Madhuri
authors.initials: M
authors.lastname: Hegde
authors.affiliation: INSERM UMR 1163, Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Université Paris Descartes, Sorbonne Paris Cité, Institut Imagine, Necker-Enfants Malades Hospital, 75015 Paris, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Colleaux
authors.affiliation: Department of Neurology, Temple University, Philadelphia, PA 19122, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Crino
authors.affiliation: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009123:Muscle Hypotonia / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D044469:Racial Groups / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; C587598:TBCK protein, human; D058570:TOR Serine-Threonine Kinases