Mendeliome
Gene: ACD Green List (high evidence)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
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
Phenotypes for gene: ACD were changed from Dyskeratosis congenita, MIM# 616553 to telomere syndrome MONDO:0100137; dyskeratosis congenita, autosomal dominant 6 MONDO:0014690; Hoyeraal-Hreidarsson syndrome MONDO:0018045
Publications for gene: ACD were set to 25205116; 25233904
Gene: acd has been classified as Green List (High Evidence).
Gene: acd has been classified as Red List (Low Evidence).
Phenotypes for gene: ACD were changed from to Dyskeratosis congenita, MIM# 616553
Publications for gene: ACD were set to
Mode of inheritance for gene: ACD was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: acd has been classified as Red List (Low Evidence).
gene: ACD was added gene: ACD was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: ACD was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.