TELO2 – TELO2-related intellectual disability–neurodevelopmental disorder

TELO2 encodes a core component of the triple T (TTT) co-chaperone complex essential for maturation and stability of phosphatidylinositol 3-kinase-related kinases (PIKKs). Biallelic TELO2 variants underlie You-Hoover-Fong syndrome (MONDO:0014848), an autosomal recessive neurodevelopmental disorder characterized by microcephaly, global developmental delay, intellectual disability, postnatal growth retardation, dysmorphic facial features and multisystem anomalies ([PMID:27132593]).

To date, 29 individuals from over 15 families have been reported with TELO2-related YHFS. Notable cases include Danish sisters with compound heterozygous splice-site and missense variants, including c.2312T>C (p.Leu771Ser) ([PMID:28944240]); siblings harboring c.1100G>T (p.Cys367Phe) ([PMID:32940098]); and an Iranian patient homozygous for c.1799A>G (p.Tyr600Cys) ([PMID:38421525]). All cases exhibit autosomal recessive inheritance with compound heterozygous or homozygous TELO2 variants and show segregation in 19 affected relatives across multiple pedigrees ([PMID:36797513]).

The TELO2 variant spectrum comprises 20 pathogenic alleles, predominantly missense substitutions (e.g., p.Cys367Phe, p.Leu771Ser), loss-of-function nonsense variants (p.Lys749Ter) and splice-site mutations (c.2227-1G>A). No recurrent founder mutations have been identified, and allele frequencies are extremely low or absent in population databases.

Functional studies in patient fibroblasts demonstrate reduced steady-state levels of TELO2 and destabilization of the TTT complex despite largely preserved PIKK signaling in cellular assays ([PMID:27132593]). In Saccharomyces cerevisiae, separation-of-function Tel2 mutants (e.g., Tel2-13) cause telomere shortening and heightened rapamycin sensitivity linked to TORC disruption, underscoring conserved pathogenic mechanisms ([PMID:22227188]).

No large-scale conflicting evidence has been reported. A single report of hepatoblastoma in a YHFS sibling pair raises the possibility of cancer predisposition, warranting surveillance but currently remains inconclusive ([PMID:39704248]).

Integration of robust genetic segregation across 19 relatives, 29 probands, and concordant functional assays supports a Strong ClinGen gene–disease association for TELO2 and YHFS. Screening for biallelic TELO2 variants is clinically useful for diagnosis, management, genetic counseling, and may inform potential cancer surveillance protocols.

References

• American Journal of Human Genetics • 2016 • A Syndromic Intellectual Disability Disorder Caused by Variants in TELO2, a Gene Encoding a Component of the TTT Complex. PMID:27132593
• Molecular genetics & genomic medicine • 2017 • Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You-Hoover-Fong syndrome. PMID:28944240
• Ophthalmic genetics • 2020 • Cataract in You-Hoover-Fong syndrome: TELO2 deficiency. PMID:32940098
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2024 • The first Iranian patient with You-Hoover-Fong syndrome and a review of the literature on 27 cases: expanding the genotypic and phenotypic spectrum. PMID:38421525
• American journal of medical genetics. Part A • 2023 • TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature. PMID:36797513
• American journal of medical genetics. Part A • 2025 • Expansion of the Phenotype of You-Hoover-Fong Syndrome and Possible Increased Risk of Cancer. PMID:39704248
• Biochemical and biophysical research communications • 2012 • Saccharomyces cerevisiae Tel2 plays roles in TORC signaling and telomere maintenance that can be mutationally separated. PMID:22227188

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