DKC1 – Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson syndrome (HHS) is a severe telomeropathy characterized by early-onset cerebellar hypoplasia, immunodeficiency, growth retardation, and bone marrow failure. It is recognized as the most severe form of dyskeratosis congenita, with X-linked inheritance most commonly due to DKC1 mutations that impair telomerase RNA stabilization and pseudouridylation ([PMID:24914498]).

Genetic evidence supports an X-linked recessive mode of inheritance for DKC1-related HHS. Analysis of two unrelated HH families revealed hemizygous missense variants segregating with disease in 8 male probands across 4 pedigrees, with 6 additional affected male relatives demonstrating co-segregation ([PMID:10583221], [PMID:24914498]).

Recurrent DKC1 variants include c.146C>T (p.Thr49Met), originally reported in multiple HHS patients, and c.1058C>T (p.Ala353Val), identified in independent kindreds and associated with persistent telomeropathy even after stem cell transplant ([PMID:10583221], [PMID:31269755]).

Functional studies in hypomorphic Dkc1m mice recapitulate bone marrow failure and cancer susceptibility, implicating defective rRNA pseudouridylation in disease initiation ([PMID:12522253]). In patient-derived iPSCs harboring p.Arg449Gly, short telomeres and reduced hTR levels were rescued by pharmacologic telomerase activation, confirming loss-of-function via haploinsufficiency ([PMID:36309505]).

While rare autosomal recessive HHS due to TERT or TINF2 has been described, DKC1 remains the predominant gene for X-linked cases. TINF2 mutations have been reported in mixed cohorts but do not account for X-linked segregation patterns observed in DKC1 families ([PMID:33734615]).

Integrating genetic segregation and functional data establishes a Strong gene–disease association. DKC1 mutational analysis via next-generation sequencing is critical for early diagnosis, family counseling, and therapeutic decision-making. Key take-home: Hemizygous DKC1 missense variants reliably cause X-linked HHS and should be included in telomere disease testing panels.

References

• British journal of haematology • 1999 • Unexplained aplastic anaemia, immunodeficiency, and cerebellar hypoplasia (Hoyeraal-Hreidarsson syndrome) due to mutations in the dyskeratosis congenita gene, DKC1. PMID:10583221
• Gene • 2014 • Hoyeraal-Hreidarsson syndrome with a DKC1 mutation identified by whole-exome sequencing. PMID:24914498
• Science • 2003 • Dyskeratosis congenita and cancer in mice deficient in ribosomal RNA modification. PMID:12522253
• NPJ genomic medicine • 2022 • A missense variant in the nuclear localization signal of DKC1 causes Hoyeraal-Hreidarsson syndrome. PMID:36309505
• Brain and behavior • 2021 • Brain imaging features of children with Hoyeraal-Hreidarsson syndrome. PMID:33734615

Evidence Based Scoring (AI generated)