TERT – Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson syndrome (HHS) is a severe autosomal recessive telomere biology disorder characterized by intrauterine growth retardation, microcephaly and cerebellar hypoplasia, along with mucocutaneous features of dyskeratosis congenita. Biallelic loss-of-function variants in the telomerase reverse transcriptase gene TERT underlie AR-HHS through critically short telomeres and impaired telomerase activity.

Multiple consanguineous and non-consanguineous families have been reported with homozygous or compound heterozygous TERT variants segregating with full-blown short telomere syndrome phenotypes. In one cohort, two unrelated probands with classical dyskeratosis congenita or HHS harbored homozygous missense variants c.2431C>T (p.Arg811Cys) and c.2701C>T (p.Arg901Trp) leading to nearly absent telomerase activity and extremely short telomeres (PMID:17785587). A separate report described two siblings with HHS due to a homozygous c.1700C>T (p.Thr567Met) TERT mutation that markedly impaired telomerase processivity (PMID:23538340). More recently, an index case from a consanguineous Turkish family was shown to carry c.2011C>T (p.Arg671Trp), with segregation of this variant in the affected child and short telomere lengths in carriers (PMID:34890115).

Overall, at least five independent probands across three families exhibit AR inheritance with segregation of TERT variants in affected relatives, confirming the gene-disease link (PMID:17785587, PMID:23538340, PMID:34890115). The variant spectrum includes missense substitutions in the reverse transcriptase and T-motif domains, with no recurrent founder alleles reported to date.

Functional studies consistently demonstrate that patient-derived cells or in vitro reconstitution of TERT mutants have dramatically reduced telomerase enzymatic activity, processivity defects, and critically short telomeres, establishing a loss-of-function mechanism of haploinsufficiency for telomere maintenance.

No significant conflicting evidence has been reported. Heterozygous carriers may develop adult-onset telomere syndromes such as pulmonary fibrosis or bone marrow failure, underscoring dose sensitivity of TERT activity.

In summary, genetic and experimental data support a strong association between biallelic TERT variants and AR HHS. Genetic testing for TERT mutations and telomere length measurement are essential for diagnosis and family counseling.

References

• Blood • 2007 • Telomerase reverse-transcriptase homozygous mutations in autosomal recessive dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome PMID:17785587
• Blood • 2013 • A homozygous telomerase T-motif variant resulting in markedly reduced repeat addition processivity in siblings with Hoyeraal Hreidarsson syndrome PMID:23538340
• American journal of medical genetics. Part A • 2022 • Biallelic TERT variant leads to Hoyeraal-Hreidarsson syndrome with additional dyskeratosis congenita findings PMID:34890115

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