De novo TLK1 and MDM1 mutations in a patient with a neurodevelopmental disorder and immunodeficiency
Marina Villamor-Payà,
María Sanchiz-Calvo,
Jordann Smak,
Lynn Pais,
Malika Sud,
Uma Shankavaram,
Alysia Kern Lovgren,
Christina Austin-Tse,
Vijay S. Ganesh,
Marina Gay,
Marta Vilaseca,
Gianluca Arauz-Garofalo,
Lluís Palenzuela,
Grace VanNoy,
Anne O’Donnell-Luria,
Travis H. Stracker
Affiliations
Marina Villamor-Payà
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, MD 20892, USA
María Sanchiz-Calvo
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Jordann Smak
National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, MD 20892, USA
Lynn Pais
Division of Genetics & Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Malika Sud
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Uma Shankavaram
National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, MD 20892, USA
Alysia Kern Lovgren
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Christina Austin-Tse
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Vijay S. Ganesh
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Neurology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Marina Gay
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Marta Vilaseca
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Gianluca Arauz-Garofalo
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Lluís Palenzuela
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Grace VanNoy
Division of Genetics & Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Anne O’Donnell-Luria
Division of Genetics & Genomics, Department of Pediatrics, Boston Children’s Hospital, Boston, MA 02115, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA
Travis H. Stracker
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, 08028 Barcelona, Spain; National Cancer Institute, Center for Cancer Research, Radiation Oncology Branch, Bethesda, MD 20892, USA; Corresponding author
Summary: The Tousled-like kinases 1 and 2 (TLK1/TLK2) regulate DNA replication, repair and chromatin maintenance. TLK2 variants underlie the neurodevelopmental disorder (NDD) ‘Intellectual Disability, Autosomal Dominant 57’ (MRD57), characterized by intellectual disability and microcephaly. Several TLK1 variants have been reported in NDDs but their functional significance is unknown. A male patient presenting with ID, seizures, global developmental delay, hypothyroidism, and primary immunodeficiency was determined to have a heterozygous TLK1 variant (c.1435C>G, p.Q479E), as well as a mutation in MDM1 (c.1197dupT, p.K400∗). Cells expressing TLK1 p.Q479E exhibited reduced cytokine responses and elevated DNA damage, but not increased radiation sensitivity or DNA repair defects. The TLK1 p.Q479E variant impaired kinase activity but not proximal protein interactions. Our study provides the first functional characterization of NDD-associated TLK1 variants and suggests that, such as TLK2, TLK1 variants may impact development in multiple tissues and should be considered in the diagnosis of rare NDDs.
