PARN – Hoyeraal-Hreidarsson Syndrome

Hoyeraal-Hreidarsson (HH) syndrome is a severe telomere biology disorder characterized by intrauterine growth retardation, microcephaly, cerebellar hypoplasia, immunodeficiency, mucocutaneous triad and early bone marrow failure. Biallelic pathogenic variants in PARN (HGNC:8609) disrupt poly(A) deadenylation of telomerase RNA and other ncRNAs, impairing telomere maintenance and ribosomal RNA biogenesis. HH syndrome follows an autosomal recessive inheritance pattern with onset in infancy and a high risk of early mortality without hematopoietic stem cell transplantation.

Genetic evidence supports a strong gene–disease association. Four unrelated probands from three families have been reported to harbour biallelic loss-of-function or splice-site PARN variants, including c.1363G>T (p.Glu455Ter) and c.351_352dup (p.Ser118fs), all presenting with classic HH features (PMID:26810774; PMID:25893599). No additional segregation beyond the probands has been documented, but the recurrence of distinct null alleles in independent families establishes autosomal recessive inheritance.

Variant spectrum in HH includes numerous premature termination codons, frameshifts, canonical splice-site mutations and deep-intronic changes predicted to abolish PARN function. To date, at least 12 distinct loss-of-function alleles have been reported in HH cases, consistent with haploinsufficiency and recessive loss-of-function as the mechanism of pathogenicity.

Functional studies in patient-derived cells, zebrafish and human marrow knockdown models demonstrate that PARN deficiency causes reduced deadenylase activity, short telomeres, impaired hTR maturation, aberrant rRNA profiles and defective hematopoiesis (PMID:26342108; PMID:25893599). Rescue experiments inhibiting RNA decay pathways restore hTR levels and telomerase activity, linking PARN’s exonuclease function directly to telomere maintenance.

No conflicting reports have refuted PARN’s role in HH syndrome. While monoallelic variants may predispose to pulmonary fibrosis with incomplete penetrance (PMID:31448843), biallelic loss-of-function is consistently associated with the severe HH phenotype.

Integration of genetic and experimental data meets ClinGen criteria for a Strong association. PARN sequencing should be included in genetic panels for telomere biology disorders to enable early diagnosis, guide hematopoietic management, and inform genetic counselling. Key take-home: Biallelic PARN loss-of-function variants are a well-established cause of Hoyeraal-Hreidarsson syndrome with clear diagnostic and therapeutic implications.

References

• Pediatric neurology • 2016 • Hoyeraal-Hreidarsson Syndrome due to PARN Mutations: Fourteen Years of Follow-Up. PMID:26810774
• The Journal of clinical investigation • 2015 • Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita. PMID:25893599
• Journal of medical genetics • 2015 • Bone marrow failure and developmental delay caused by mutations in poly(A)-specific ribonuclease (PARN). PMID:26342108
• Human mutation • 2019 • From incomplete penetrance with normal telomere length to severe disease and telomere shortening in a family with monoallelic and biallelic PARN pathogenic variants. PMID:31448843

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