Rare anaemia
Gene: ADH5Comment on list classification: New gene added by Zornitza Stark. Sufficient unrelated cases (>3) with relevant phenotype for this panel; however, as inheritance is digenic, this gene has been made Amber rather than Green and tagged 'digenic'.Created: 4 Jan 2021, 12:27 p.m. | Last Modified: 4 Jan 2021, 12:27 p.m.
Panel Version: 1.7
Currently not associated with any phenotype in OMIM or Gene2Phenotype.
At least 17 individuals from 15 unrelated Japanese families reported with an inherited bone marrow failure syndrome associated with biallelic variants in the ADH5 gene (PMIDs: 33147438 and 33355142). Relatively consistent clinical presentation characterised by aplastic anaemia, cognitive impairment, skin hyperpigmentation, short stature and microcephaly.
Supportive in vitro and in vivo studies indicate the observed hematopoietic abnormalities may result from overload of formaldehyde-induced DNA damage due to deficiency of endogenous formaldehyde clearance mechanisms.
All affected patients additionally harboured at least one copy of the ALDH2 rs671 defective allele (G/A or A/A) indicating a digenic cause. One healthy individual identified with a homozygous ADH5 variant but wild-type ALDH2, suggesting that loss of ADH5 alone is not sufficient for pathogenesis - supported by functional data (PMID: 33355142).Created: 4 Jan 2021, 12:22 p.m. | Last Modified: 4 Jan 2021, 12:22 p.m.
Panel Version: 1.6
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Aplastic anaemia; Mental retardation; Skin hyperpigmentation, Short stature; Microcephaly
Publications
7 individuals reported with bi-allelic variants in this gene and a Fanconi syndrome-like phenotype. All had aplastic anaemia, 4 developed a myelodysplastic syndrome, and one developed AML. Short stature and abnormal skin pigmentation were additional features.
Note, all also had the ALDH2*2 allele, which is common in East Asian populations, and may be contributory.
Extensive experimental data.
Sources: LiteratureCreated: 9 Dec 2020, 6:13 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Aplastic anaemia; myelodysplasia; short stature
Publications
Phenotypes for gene: ADH5 were changed from Aplastic anaemia; myelodysplasia; short stature to Aplastic anaemia; Mental retardation; Skin hyperpigmentation, Short stature; Microcephaly
Publications for gene: ADH5 were set to 33147438
Gene: adh5 has been classified as Amber List (Moderate Evidence).
Tag digenic tag was added to gene: ADH5.
gene: ADH5 was added gene: ADH5 was added to Rare anaemia. Sources: Literature Mode of inheritance for gene: ADH5 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ADH5 were set to 33147438 Phenotypes for gene: ADH5 were set to Aplastic anaemia; myelodysplasia; short stature Review for gene: ADH5 was set to GREEN