Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly

Am J Hum Genet. 2023 Mar 2;110(3):499-515. doi: 10.1016/j.ajhg.2023.01.006. Epub 2023 Jan 31.


Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

Keywords: TTI1 gene; autosomal recessive; consanguinity; gene; mendelian disorders; microcephaly; neurodevelopment; pathogenic variants.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Microcephaly*
  • Movement Disorders*
  • Neurodevelopmental Disorders*
  • TOR Serine-Threonine Kinases


  • Intracellular Signaling Peptides and Proteins
  • TOR Serine-Threonine Kinases