Hereditary Pigmentary Disorders

Gene: ACD

Green List (high evidence)

ACD (ACD, shelterin complex subunit and telomerase recruitment factor)
EnsemblGeneIds (GRCh38): ENSG00000102977
EnsemblGeneIds (GRCh37): ENSG00000102977
OMIM: 609377, Gene2Phenotype
ACD is in 4 panels

2 reviews

Bryony Thompson (Royal Melbourne Hospital)

Green List (high evidence)

Biallelic - 4 families (3 with compelling evidence) and a supportive mouse model. Loss of function is the mechanism of disease.
1 - PMID: 25233904 - a proband with Hoyeraal-Hreidarsson syndrome compound heterozygous for Lys170del and P491T, resulting in extremely short telomeres and a severe clinical phenotype. Probands sibling and mother heterozygous for Lys170del also had <1st centile. The in-frame deletion compromises both telomerase recruitment and processivity, while the missense variant is not clearly deleterious in functional assays.
1 - PMID: 33446513 - individual with compound heterozygous NM_001082486.1:c.505_507delGAG, p.(Glu169del) and NM_001082486.1:c.619delG, p.(Asp207Thrfs*22). Phenotype: 2 yr of age with clinical features that included intrauterine growth restriction, microcephaly, failure to thrive, speech delay, severe B-cell deficiency with associated life-threatening infections, severe enteropathy, and hypocellular bone marrow. Proband had telomere length <1st centile, the heterozygous parent with the in-frame deletion had a telomere length <10th centile, and parent/sibling with the frameshift variant had telomere length ~50th centile. Also a de novo large deletion including ACD reported, but another gene in the deletion was determined to contribute to the patients phenotype. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features.
2 - PMID: 30064976 - 2 homozygous missense variants identified in consanguineous families. c.280C>T; p.V94I identified in a 38 yo with thrombocytopenia, short stature, pulmonary abnormalities, and LSCD with telomere length just below the 10th centile, but 3 homozygotes present gnomAD. c.284T>A, p.L95Q identified in a 12 yo with leukoplakia and subsequently developed BMF and immunodeficiency with very short telomeres (parents also had short telomeres but asymptomatic). In vitro assays demonstrated impaired TERT binding and telomerase activity for both variants, but L95Q was more deficient than V94I.
PMID: 24316971 - null mouse model is embryonic lethal. Haematopoietic stem cells from the mice with complete Acd inactivation underwent cell cycle arrest, and were severely depleted within days, leading to hematopoietic failure.

Monoallelic - moderate (amber) evidence suggesting a different mechanism to the recessive disease
PMID: 25205116 - Lys170del identified in 18-yo proband, mother, and maternal grandmother presented with bone marrow failure of varying severity, and decreasing ages of presentation in successive generations. All with short telomeres. In vitro assays demonstrate the variant localises to telomeres but fails to recruit telomerase to telomeres.
PMID: 27528712 - c.752-2A>C identified in 2 individuals with CLL from a single family. Their telomere lengths of the cases displayed no obvious trends.
PMID: 30995915 - heterozygous p.P16Q identified in a 1 yo with pancytopenia, bone marrow failure chromosome 7 monosomy, and PBMC telomere lengths <10% aged population. Variant also present in the mother that reports several relatives affected with DC. The second variant, p.V94I is previously reported in a homozygous individual and is too common in gnomAD for dominant disease. It was identified in an infant with Immunodeficiency, myelodysplastic syndrome, chromosome 7 monosomy, and PBMC telomere length <1% aged population
PMID: 31515401 - proband 1 with bone marrow failure and pulmonary fibrosis in the context of a telomere syndrome heterozygous for recurrent p.Lys170del. Proband 2 with idiopathic pulmonary fibrosis heterozygous for p.Lys170Glu. Proband 3 with idiopathic pulmonary fibrosis heterozygous for p.Ala72Glu (9 hets in gnomAD), which was also found in the unaffected 83 yo father. All patients had a leukocyte telomere length <1st percentiles for age.
PMID: 27807141 - in vitro functional assays suggesting that the recurrent variant p.Lys170del is sufficient to cause the cellular underpinnings of dyskeratosis congenita, acting in a dosage-dependent mechanism rather than dominant-negative.
Created: 4 May 2023, 8:17 a.m. | Last Modified: 4 May 2023, 8:17 a.m.
Panel Version: 1.855

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045

Publications

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Red List (low evidence)

One family reported with each MOI.
Created: 19 Jun 2021, 2:06 a.m. | Last Modified: 19 Jun 2021, 2:06 a.m.
Panel Version: 0.8073

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Dyskeratosis congenita, MIM# 616553

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Sources
  • Expert Review Green
  • Literature
  • Victorian Clinical Genetics Services
Phenotypes
  • ACD-related short telomere syndrome MONDO:0100569
OMIM
609377
Clinvar variants
Variants in ACD
Penetrance
None
Publications
Panels with this gene

History Filter Activity

30 May 2025, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

Gene: acd has been classified as Green List (High Evidence).

30 May 2025, Gel status: 3

Entity classified by Genomics England curator

Bryony Thompson (Royal Melbourne Hospital)

Gene: acd has been classified as Green List (High Evidence).

30 May 2025, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Bryony Thompson (Royal Melbourne Hospital)

gene: ACD was added gene: ACD was added to Hereditary Pigmentary Disorders. Sources: Literature Mode of inheritance for gene: ACD was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: ACD were set to 27807141; 31515401; 30995915; 27528712; 25205116; 24316971; 30064976; 33446513; 25233904 Phenotypes for gene: ACD were set to ACD-related short telomere syndrome MONDO:0100569