TELO2‐related syndrome (You‐Hoover‐Fong syndrome): Description of 14 new affected individuals and review of the literature

Abstract

You‐Hoover‐Fong syndrome (YHFS) is an autosomal recessive condition caused by pathogenic variants in the TELO2 gene. Affected individuals were reported to have global developmental delay, intellectual disability, microcephaly, dysmorphic facial features, ocular involvement including cortical visual impairment, strabismus, cataract and rotatory nystagmus, movement disorder, hypertonia and spasticity, balance disturbance and ataxia, and abnormal sleep pattern. Other features reported include poor growth, cleft palate, cardiac malformations, epilepsy, scoliosis, and hearing loss. To date, 12 individuals with YHFS have been reported in the literature. Here we describe 14 new individuals with YHFS from 10 families. Their clinical presentation provides additional support of the phenotype recognized previously and delineates the clinical spectrum associated with YHFS syndrome. In addition, we present a review of the literature including follow‐up data on four previously reported individuals with YHFS.

Transcriptomic analysis of the Brazilian blind characid, Stygichthys typhlops, reveals convergent selection with Astyanax mexicanus and other cavefishes

“…Seven genes associated with vision exhibited convergent, relaxed selection, including TELO2, which has been implicated in cortical visual impairment and cataracts (Albokhari et al, 2023), and PCIF1, which has been associated with binocular phenotypes in vertebrates (Bosten et al, 2015). Additionally, in fishes and other vertebrates, the circadian system plays a crucial role in regulating important genes in metabolic pathways, creating a two-way relationship between circadian clocks and metabolic signals (Froland and Whitmore, 2019).…”

TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy

“…Unlike the pleiotropic phenotypes of tel2 mutants in the model organisms described in the early studies, non-lethal mutations in any one of the TTT components mainly cause intellectual disability and neuronal and physical deformities in humans, which is consistent with their interdependency as a single functional unit. Individuals with compound heterozygous of several rare variants such as C367F, D720V, and R609H in Tel2 have been linked to the You-Hoover-Fong syndrome characterized by intellectual disability, global developmental delay, dysmorphic facial features, microcephaly, abnormal movements, and abnormal auditory and visual function [14,15,[127][128][129]. Missense mutations within human Tti2 cause an autosomal recessive disorder defined by intellectual disability, microcephaly, short stature, behavioral problems, skeletal abnormalities, and facial dysmorphic features [16,130,131].…”

“…Structural studies have revealed the TTT structure as a single entity or in complex with the R2TP (Rvb1-Rvb2-Tah1-Pih1) [11][12][13], the complex that interacts with Hsp90. A series of mutations have been identified in the TTT that cause the neurodevelopmental syndrome characterized by intellectual disability, global developmental delay, microcephaly, abnormal movements, and various other pathogenic phenotypes [14][15][16][17]. Very recently, Tel2 in the TTT complex has been found to be a target of ivermectin (IVM) [18], an antiparasitic drug that has been successfully used in clinics during the past decades.…”

Exploring the Functional Roles of Telomere Maintenance 2 in the Tumorigenesis of Glioblastoma Multiforme and Drug Responsiveness to Temozolomide

“…Thus, TELO2 and the R2TP (RUVBL1, RUVBL2, PIH1D1, and RPAP3) complex function in NMD alongside DNA damage signaling [6]. The importance of TELO2-TTI1-TTI2 (TTT) assembly is illustrated by its association with syndromic intellectual disability and You-Hoover-Fong syndrome, which are caused by mutations of TTI1 and TELO2, respectively [14,15]. Loss-of-function variants in the human TELO2 gene have been linked to You-Hoover-Fong syndrome [14,15].…”

“…The importance of TELO2-TTI1-TTI2 (TTT) assembly is illustrated by its association with syndromic intellectual disability and You-Hoover-Fong syndrome, which are caused by mutations of TTI1 and TELO2, respectively [14,15]. Loss-of-function variants in the human TELO2 gene have been linked to You-Hoover-Fong syndrome [14,15]. Surprisingly, You-Hoover-Fong syndrome patients lack hallmarks of a DNA repair syndrome, such as cancer and premature aging.…”