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

TitleBi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.
Publication TypeJournal Article
Year of Publication2023
AuthorsSerey-Gaut, M, Cortes, M, Makrythanasis, P, Suri, M, Taylor, AMR, Sullivan, JA, Asleh, AN, Mitra, J, Dar, MA, McNamara, A, Shashi, V, Dugan, S, Song, X, Rosenfeld, JA, Cabrol, C, Iwaszkiewicz, J, Zoete, V, Pehlivan, D, Akdemir, ZCoban, Roeder, ER, Littlejohn, ROkashah, Dibra, HK, Byrd, PJ, Stewart, GS, Geckinli, BB, Posey, J, Westman, R, Jungbluth, C, Eason, J, Sachdev, R, Evans, C-A, Lemire, G, VanNoy, GE, O'Donnell-Luria, A, Mau-Them, FTran, Juven, A, Piard, J, Nixon, CYee, Zhu, Y, Ha, T, Buckley, MF, Thauvin, C, Umanah, GKEssien, Van Maldergem, L, Lupski, JR, Roscioli, T, Dawson, VL, Dawson, TM, Antonarakis, SE
JournalAm J Hum Genet
Date Published2023 Jan 23

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.

Alternate JournalAm J Hum Genet
PubMed ID36724785