ACD – Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita that includes cerebellar hypoplasia (HP:0001321), immunodeficiency (HP:0002721), and intrauterine growth retardation (HP:0001511). In a single family (PMID:25233904), the proband presented with extreme telomere shortening and fulfilled the HH clinical criteria. Exome sequencing identified compound heterozygosity for two ACD variants: c.250_252del (p.Lys84del) inherited paternally and c.1213C>A (p.Pro405Thr) inherited maternally. Functional assays demonstrated that the p.Lys84del deletion in the TEL patch of TPP1 severely impairs telomerase recruitment and processivity, consistent with a loss-of-function mechanism (PMID:25233904).

Given evidence from a single AR case, the gene–disease association is scored as Limited. Genetic evidence is limited to one proband with compound heterozygosity, and functional studies provide Moderate support by showing that disruption of the TEL patch compromises telomerase activity. Additional unrelated cases, segregation data, and replication of functional findings are required to strengthen clinical validity. Key take-home: consider ACD sequencing in patients with HH phenotype and very short telomeres to confirm diagnosis and guide genetic counseling.

References

• Genes & development • 2014 • Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1. PMID:25233904

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