Fetal anomalies
Gene: ACTB
PMID: 22366783 reports monoallelic variants in ACTB in 11 unrelated probands with Baraitser-Winter syndrome. A dominant-negative or gain of function mechanism is postulated, based on the lack of deletions and truncating variants and the fact that the same amino acid is disrupted in multiple cases. Baraitser-Winter syndrome is associated with intellectual disability, ocular colobomata, lissencephaly, dysmorphic features, seizures, hearing loss, postnatal short stature and microcephaly. Cleft lip/palate and CAKUT are also seen. Some of these features may be detectable antenatally (see PMID:26275891). PMID: 29220674 reports monoallelic loss of function variants in 33 unrelated individuals with developmental delay/intellectual disability, dysmorphic features and growth retardation. Some cases had structural anomalies, most commonly CAKUT and/or congenital heart defects.Created: 2 Jan 2019, 9:13 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Baraitser-Winter syndrome 1
Publications
Additional evidence from PAGE study: Potentially clinically useful variant identified in this gene from fetalexome sequencing inLord et al., 2019 (PMID:30712880).Created: 18 Apr 2019, 3:51 p.m.
This gene and phenotype were reviewed during meetings at Great Ormond Street hospital in March 2019. Clinical review and curation was performed by Lyn Chitty, Anna de Burca, Rhiannon Mellis, Richard Scott, Ellen McDonagh and Rebecca Foulger. Outcome of review: Confirmed that phenotype is fetally-relevant: keep on the Fetal anomalies panel as a Green gene.Created: 4 Apr 2019, 2:03 p.m.
Removed watchlist tag following clinical review by Anna de Burca.Created: 7 Jan 2019, 10:33 a.m.
Comment on list classification: Updated rating from Amber to Green following review and email correspondance from Anna de Burca. Originally assigned an Amber rating because of different PAGE/DDG2P ratings for different disorders. As summarised by Anna there is good evidence for GOF variants causing Baraitser-Winter syndrome plus some evidence for LOF variants associated (in some cases) with structural anomalies.Created: 7 Jan 2019, 10:32 a.m.
Comment on mode of pathogenicity: Anna notes that there is good evidence for GOF variants causing Baraitser-Winter syndrome but there is also a paper from DDD (PMID:29220674) reporting LOF variants associated predominantly with developmental delay but in some cases structural anomalies including congenital heart defects and/or CAKUT- this may not be a severe enough prenatal phenotype for inclusion in a fetal panel but overall Anna notes that it is probably reasonable to report any variants in this gene, whether GOF or LOF. Therefore no exception to LOF was added to the MOP section.Created: 7 Jan 2019, 10:30 a.m.
Comment on mode of inheritance: Changed MOI to 'NOT imprinted' based on Anna's review.Created: 7 Jan 2019, 10:29 a.m.
'watchlist' tag added to highlight different DD-G2P ratings for this gene.Created: 8 Nov 2018, 8:54 p.m.
In the original PAGE file: rated as Confirmed for BARAITSER-WINTER SYNDROME, and rated as Probable for ACTB Haploinsufficiency syndtome. In the original PAGE file, MOP listed as All missense/in frame for BARAITSER-WINTER SYNDROME, and listed as LOF for ACTB Haploinsufficiency syndtome.Created: 8 Nov 2018, 4:45 p.m.
Publications
Tag watchlist was removed from gene: ACTB.
Gene: actb has been classified as Green List (High Evidence).
Mode of pathogenicity for gene: ACTB was changed from to None
Mode of inheritance for gene: ACTB was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Tag watchlist tag was added to gene: ACTB.
Added phenotypes ACTB Haploinsufficiency syndtome for gene: ACTB
gene: ACTB was added gene: ACTB was added to Fetal anomalies. Sources: PAGE DD-Gene2Phenotype,Expert Review Amber Mode of inheritance for gene: ACTB was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Phenotypes for gene: ACTB were set to BARAITSER-WINTER SYNDROME