Intellectual disability - microarray and sequencing
Gene: AHCY
Comment on list classification: DD may occasionally be mild, however is an early and consistent finding amongst surviving patients. Inclusion on this panel may benefit detection of patients who would otherwise not be considered for testing via other routes (e.g. where metabolic abnormalities become apparent later).
Therefore, recommending a GREEN rating at the next major review.Created: 25 Sep 2020, 11:35 a.m. | Last Modified: 25 Sep 2020, 11:35 a.m.
Panel Version: 3.337
Added 'treatable' tag as some patients have shown improvement following dietary management (particularly methionine restriction and supplementation with creatine and phosphatidylcholine)Created: 25 Sep 2020, 11:27 a.m. | Last Modified: 25 Sep 2020, 11:27 a.m.
Panel Version: 3.336
- PMID: 15024124 (2004), 16435181 (2005) - Two brothers with S-adenosylhomocysteine hydrolase (SAHH) deficiency, and elevated levels of plasma creatine kinase (CK), S-adenosylhomocysteine (AdoHcy), S-adenosylmethionine (AdoMet) and methionine, due to compound het variants (c.336G>A, p.W112X and c.428A>G, p.Y143C) in AHCY. Authors note psychomotor delay, delayed myelination, hypotonia, poor head control, and mild hepatitis-like findings in one sib. [Note: the group also reported on a third brother who resembled the previous cases (https://www.bib.irb.hr/346457), but the article is not in PubMed and full text is unavailable].
- PMID: 16736098 (2006) - 26-year-old male with severe myopathy, hypotonia, DD, and elevated CK, AdoMet and hypermethioninaemia due to SAHH deficiency associated with compound het variants (c.428A>G, p.Y143C and c.266C>T, p.A89V) in AHCY. At 20 years, WAIS testing showed a verbal IQ score of 76, performance IQ 56, and full scale IQ 64.
- PMID: 20852937 (2010) - Two sibling sisters born with fetal hydrops, insufficient liver synthetic function and muscular hypotonia leading to respiratory failure and death in early infancy. Both had anomalies on brain MRI, including hypomyelination, and metabolic abnormalities resembling previously described cases. Deficient SAHH activity due to compound het variants (c.145C>T, p.R49C and c.257A>G; p.D86G) in AHCY was identified. Functional analysis of both variants (PMID: 19177456) showed reduced protein stability and enzymatic inactivation, respectively.
- PMID: 22959829 (2012) - One patient with SAHH deficiency due to compound het variants (c.145C>T, p.R49C and c.211G>A, p.G71S) in AHCY. Clinical characteristics included hypotonia, severe DD (corresponding to a 6-month infant at 4.5-years of age) and progressive hepatopathy, but normal brain MRI. Plasma methionine and homocysteine levels were normal during the neonatal period and increased only after 8 months of age.
- PMID: 26095522 (2015) - One child with SAHH deficiency (AHCY c.428A>G, p.Y143C and c.982T>G, p.Y328Asp) presented at 8 months of age with growth failure, microcephaly, GDD, myopathy, hepatopathy, and factor VII deficiency. Metabolic abnormalities included elevated plasma methionine, AdoHcy and AdoMet.
- PMID: 26527160 (2015) - Homozygous missense variant (c.146G>A, p.R49H) in AHCY identified post-mortem in a 32-year-old woman with elevated aminotransferase and hepatocellular carcinoma. The same variant was detected in her son who had elevated serum levels of aminotransferase, AdoHcy, AdoMet, and methionine (hallmarks of SAHH def), but remained asymptomatic at 7-years-old.
- PMID: 28779239 (2017) - Compound het variants (c.266C>T, p.A89V and c.428A>G, p.Y143C) identified in an infant, who presented following birth with hypotonia, poor sucking reflex, apnea episodes and rhabdomyolysis (no further info available).
- PMID: 30121674 (2018) - Infant with a prenatal diagnosis of non-immune hydrops, hypotonia, poor respiratory effort, chylothorax, encephalopathy, coagulopathy, progressive hepatic failure, and refractory pulmonary hypertension. Life support was withdrawn at 7 days. Novel compound het variants (p.E108K and p.Y328D) in AHCY were found.
- PMID: 31957987 (2020) - One child with compound het variants (c.170C>T, p.T57I and c.649G>A, p.V217M) in AHCY. The patient presented foetal hydrops, diffuse oedema, coagulopathy, CNS abnormalities, and hypotonia. She died in 3 months due to cardiovascular collapse. Metabolic parameters showed normal methionine levels, but AdoMet and AdoHcy could not be measured.Created: 25 Sep 2020, 11:22 a.m. | Last Modified: 25 Sep 2020, 11:22 a.m.
Panel Version: 3.336
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, 613752
Publications
Multiple affected individuals reported, DD/ID is part of the phenotype.Created: 27 Jan 2020, 6:06 a.m. | Last Modified: 27 Jan 2020, 6:06 a.m.
Panel Version: 3.0
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, MIM#613752
Publications
The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 9 Mar 2022, 3:40 p.m. | Last Modified: 9 Mar 2022, 3:40 p.m.
Panel Version: 3.1510
Two variants reported as compound heterozygotes in one case.Created: 31 Oct 2017, 9:57 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Publications
Tag for-review was removed from gene: AHCY.
Source Expert Review Green was added to AHCY. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Publications for gene: AHCY were set to 15024124
Gene: ahcy has been classified as Amber List (Moderate Evidence).
Tag for-review tag was added to gene: AHCY.
Tag treatable tag was added to gene: AHCY.
12.03.2018: Due to major updates completed (Phase 1, 2 and 3), this panel was promoted to Version 2 in order to reflect the major updates since November 2017 which have resulted in reviews for 836 genes added by Genomics England Curators and the Clinical Team, 130 new Green genes added to the interpretation pipeline (from 751 to 881 Green genes), and the gene total has increased from 1879 to 1927.
Model of inheritance for gene AHCY was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene AHCY was set to ['15024124']
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
AHCY was added to Intellectual disabilitypanel. Source: Expert Review Red
AHCY was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen