Submission Details

ACD was first reported in relation to semidominant ACD-related short telomere syndrome in 2014 (Kocak et al., PMID: 25233904). ACD encodes one of the six core proteins of the shelterin complex that coats telomeres. This complex functions to regulate telomerase and telomere end protection (PMID: 32674474). Individuals with variants in ACD have variable phenotypes including oral leukoplakia, nail dystrophy, abnormal skin pigmentation, premature graying of the hair, cerebellar hypoplasia, bone marrow failure, aplastic anemia, pulmonary fibrosis, and short telomere length (PMIDs: 30064976, 30995915, 31515401). Pulmonary phenotypes have been seen both in isolation and as part of a syndromic presentation (PMID: 31515401). There is typically a pediatric age of onset for patients with a diagnosis of Hoyeraal-Hreidarsson syndrome or dyskeratosis congenita, whereas there is an adult age of onset for patients with pulmonary fibrosis.

Variants in ACD have been reported in individuals with the following disease entities: dyskeratosis congenita, autosomal dominant 6, dyskeratosis congenita, autosomal recessive 7, Hoyeraal-Hreidarsson syndrome, hereditary isolated aplastic anemia, and pulmonary fibrosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, ACD-related short telomere syndrome (OMIM: 616553). Of note, this gene has also been implicated in familial melanoma and long telomeres. Variants associated with long and short telomeres are distinct and the long telomere phenotype will be assessed separately.

Nine variants (6 missense, 2 in-frame indels, 1 frameshift) that have been reported in 10 probands across 6 publications (PMIDs: 25233904, 25205116, 30064976, 31515401, 30995915, 33446513) are included in this curation. The mechanism of pathogenicity is reported to be loss of function.

This gene-disease relationship is also supported by biochemical function assays, expression studies, functional alteration assays, cell culture models, animal models, and rescue models (PMIDs: 33446513, 25205116, 27807141, 25128433, 15537664).

In summary, there is definitive evidence supporting the relationship between ACD and semidominant ACD-related short telomere syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Interstitial Lung Disease GCEP on the meeting date February 20, 2024 (SOP Version 10).