Intellectual disability - microarray and sequencing
Gene: ABCC9
Comment on mode of pathogenicity: Loss of function variants do cause the phenotype of Intellectual disability and myopathy syndrome (OMIM:619719) , which is relevant to this panel.Created: 6 Feb 2024, 4:12 p.m. | Last Modified: 6 Feb 2024, 4:12 p.m.
Panel Version: 5.448
Seven homozygous loss of function ABCC9 variants have been reported in seven unrelated cases of Intellectual disability and myopathy syndrome (OMIM:619719)(PMID: 31575858; 38217872). In vivo studies of abcc9 LoF in zebrafish, revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility.(PMID: 38217872). Heterozygous parents of the cases, did not show a consistent phenotype, although intrauterine death was reported in two families (PMID: 38217872). In family 4 the fetus was homozygous for c.1858C>T, p.(Arg620Ter) and in family 8 the parents were both heterozygous for c.2140_2141del, p.(Leu714SerfsTer7), but analysis of the fetus was not possible.Created: 6 Feb 2024, 3:34 p.m. | Last Modified: 6 Feb 2024, 3:44 p.m.
Panel Version: 5.445
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability and myopathy syndrome, OMIM:619719; intellectual disability and myopathy syndrome, MONDO:0859224
Publications
This gene is currently green for monoallelic inheritance but the associated review relates to cases with biallelic inheritance. The MOI for this gene should be amended to biallelic only. Monoallelic variants are associated with Cantu syndrome which is not primarily an ID disorder or DCM.Created: 6 Feb 2024, 4:57 p.m. | Last Modified: 6 Feb 2024, 4:57 p.m.
Panel Version: 5.449
This gene is currently green on the ID panel for monoallelic inheritance. Monoallelic variants in this gene are associated with Cantu syndrome, which is primarily characterised by hypertrichosis, facial dysmorphism and heart defects. According to genereviews ' Developmental delays are common, but intellect is typically normal; behavioral problems can include attention-deficit/hyperactivity disorder, autism spectrum disorder, obsessive-compulsive disorder, anxiety, and depression.' Therefore this gene probably should not be green for this disorder on the ID panel. There is some evidence for biallelic variants being associated with ID but insufficient data currently for this to be elevated to green for biallelic inheritance - suggest downgrading to amber for biallelic inheritance onlyCreated: 25 Jan 2024, 10:07 a.m. | Last Modified: 25 Jan 2024, 10:07 a.m.
Panel Version: 5.409
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Variants in this GENE are reported as part of current diagnostic practice
Comment on list classification: Intellectual impairment has been reported in individuals with loss-of-function variants and a percentage of those with gain-of-function variants. ID is typically mild, however it is plausible that patients may still be tested for this panel, particularly if recruited under Coffin-Siris-like coarse facial features which can be associated with this gene. Therefore, maintaining Green gene rating.
Comment on mode of inheritance: Leaving MOI as Monoallelic as only 2 families with the same biallelic variant (possible founder variant) reported to date (PMID:31575858), and patients with biallelic variants would still be picked up by the Genomics England pipeline.Created: 22 Jan 2021, 10:41 a.m. | Last Modified: 26 Jan 2021, 11:48 a.m.
Panel Version: 3.740
Copied from review by Tracy Lester (Genetics laboratory, Oxford UK) on the DDG2P panel, 14 Jul 2020:
"Authors report 6 cases from 2 families, all with homozygous c.1320+1G>A. Phenotype of mild ID, similar facies, myopathy, cerebral white matter hyperintensities, and cardiac systolic dysfunction in the oldest cases.
'This mutation results in an in-frame deletion of exon 8, which results in non-functional KATP channels in recombinant assays. SUR2 loss-of-function causes fatigability and cardiac dysfunction in mice, and reduced activity, cardiac dysfunction and ventricular enlargement in zebrafish. We term this channelopathy resulting from loss-of-function of SUR2-containing KATP channels ABCC9-related Intellectual disability Myopathy Syndrome (AIMS). The phenotype differs from Cantú syndrome, which is caused by gain-of-function ABCC9 mutations, reflecting the opposing consequences of KATP loss- versus gain-of-function'.
Just 2 families so doesn't fulfil criteria for green gene yet in terms of ID - amber"Created: 22 Jan 2021, 10:16 a.m. | Last Modified: 22 Jan 2021, 10:16 a.m.
Panel Version: 3.717
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
mild ID; similar facies, myopathy; cerebral white matter hyperintensities; cardiac systolic dysfunction
Publications
Phenotypes
CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA
This is a pertinent gene from the NIHR BioResource - Rare Diseases Study (NIHRBR-RD) BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene is on the SPEED_NEURO_20170705 gene list. Evidences used for SPEED NEURO gene list: in_ddg2p_20141118_conf;in_ddg2p_20141118_conf;in_ddg2p_201507;in_ddg2p_201507_conf;in_ddg2p_2_4_2017;in_ddg2p_2_4_2017_conf;in_gilissen_2014_known;in_UKGTN_v12 . Main mutation mechanism : ActivatingCreated: 27 Jul 2017, 4:57 p.m.
Evidences key, gene present in following gene lists and main mutation mechanism : ddg2p_20141118; ddg2p_20141118_conf; ddg2p_201507; ddg2p_201507_conf; gilissen_2014_known; UKGTN_v12; Nijmegen_ID_diagnostic; Nijmegen_ID_candidates; GEL_ID_red_20160217; neuro_20160418_strict; Activating. This is a pertinent gene from the BRIDGE Study : SPEED (Specialist Pathology: Evaluating Exomes in Diagnostics) which covers epilepsies, movement and microcephaly disorders, this gene comes from the SPEED_NEURO_v3.0_20170404 gene list. The following experts from the BRIDGE consortium NIHRBR-RD contributed to this panel: - Professor F. Lucy Raymond, Cambridge Institute for Medical Research, University of Cambridge - Manju Kurian, Paediatric neurologist, Great Ormond Street Hosptial - Keren Carss, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Alba Sanchis-Juan, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Marie Erwood NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation Trust - Louise Daugherty, NIHR BioResource - Rare Diseases, Cambridge University Hospitals NHS Foundation TrustCreated: 19 Jul 2017, 11:54 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
Mode of pathogenicity
Other
This was promoted from red to green due to application to patients recruited under coarse facial features including Coffin-Siris-like disorders.Created: 28 Nov 2016, 1:51 p.m.
Comment on list classification: A minority of affected individuals will have some intellectual disability. Mild motor delay common due to hypotoniaCreated: 28 Nov 2016, 1:42 p.m.
Comment on list classification: A minority of affected individuals will have some intellectual disability. Mild motor delay common due to hypotoniaCreated: 28 Nov 2016, 1:42 p.m.
Phenotypes
Cantu
Mode of pathogenicity for gene: ABCC9 was changed from None to None
Mode of pathogenicity for gene: ABCC9 was changed from Other to None
Mode of pathogenicity for gene: ABCC9 was changed from to Other
Tag watchlist_moi was removed from gene: ABCC9. Tag Q1_24_MOI tag was added to gene: ABCC9. Tag Q1_24_NHS_review tag was added to gene: ABCC9.
Phenotypes for gene: ABCC9 were changed from Cardiomyopathy, dilated, 10, 608569; Atrial fibrillation, familial, 12, 614050; Hypertrichotic osteochondrodysplasia, 239850; CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA to Intellectual disability and myopathy syndrome, OMIM:619719; intellectual disability and myopathy syndrome, MONDO:0859224
Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858; 38217872
Publications for gene: ABCC9 were set to 25529582; 24896178; 31575858
Publications for gene: ABCC9 were set to
Tag watchlist_moi tag was added to gene: ABCC9.
Tag for-review was removed from gene: ABCC9.
Gene: abcc9 has been classified as Green List (High Evidence).
Tag for-review tag was added to gene: ABCC9.
Source Victorian Clinical Genetics Services was added to ABCC9.
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.
Phenotypes for ABCC9 were set to Cardiomyopathy, dilated, 10, 608569; Atrial fibrillation, familial, 12, 614050; Hypertrichotic osteochondrodysplasia, 239850; CANTU SYNDROME HYPERTRICHOTIC OSTEOCHONDRODYSPLASIA
Mode of inheritance for ABCC9 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Mode of inheritance for ABCC9 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
This gene has been classified as Green List (High Evidence).
The Gel status was updated for this whole panel
The Gel status was updated for this whole panel
ABCC9 was added to Intellectual disabilitypanel. Source: Expert Review Red
ABCC9 was added to Intellectual disabilitypanel. Sources: Radboud University Medical Center, Nijmegen