Clefting
Gene: GDF11
The rating of this gene has been updated to Green following NHS Genomic Medicine Service approval.Created: 1 Feb 2023, 5:13 p.m. | Last Modified: 1 Feb 2023, 5:13 p.m.
Panel Version: 3.5
Comment on list classification: Promoting from grey to amber but with a recommendation for green rating following GMS review. 2 cases plus mouse model data.Created: 12 Oct 2021, 1:42 p.m. | Last Modified: 12 Oct 2021, 1:42 p.m.
Panel Version: 2.54
There is a provisional association with ?Vertebral hypersegmentation and orofacial anomalies #619122 (AD) in OMIM based on the report in PMID: 31215115.
2 confirmed cases, but 2 other possible cases plus mouse data.
In PMID 3411300 - Ravenscroft et al 2021 - 3 out of 6 affected patients are reported to have palate abnormalities but only 1(proband 2) is reported to have cleft lip and palate. The other two have a high palate. All have heterozygous loss of function or missense variants in GDF11.
In PMID 31215115 - Cox et al 2015- 3 of the 6 affected members of family 4527 had cleft lip/palate (2 unilateral left cleft lip and palate, 1 submucous cleft palate. A missense variant in GDF11 was confirmed as heterozygous in 5 affected individuals and as not present in 5 unaffected individuals, supporting an autosomal dominant mode of inheritance.
PMID: 10391213 - McPherron et al 1999 - Gdf11-null mice die within 24 hours of birth, and nearly all mutants had a range of palate and renal anomalies.
In the International Mouse Phenotyping Consortium database gdf11 knock out mice show cleft palate as a signficant phenotype https://www.mousephenotype.org/data/genes/MGI:1338027#phenotypesTab.
Also
PMID: 34061439 - Li et al 2021 - sequenced SHH, RORA, MRPL53, ACVR1 and GDF11 in1255 multi-ethnic cleft lip with/without palate and cleft palate only patients. 2 rare variants, 1 missense and 1 stop gain, found in 2 patients, however other family members also carry them (in 1 case unaffected twin, in other case mother but not clear if affected or not).Created: 12 Oct 2021, 1:35 p.m. | Last Modified: 12 Oct 2021, 1:35 p.m.
Panel Version: 2.51
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Publications
PMID 34113007: Ravenscroft et al. (2021) report 6 probands who presented with craniofacial (5/6), vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6), and connective tissue abnormalities (3/6). They found de novo and inherited variants in GDF11. gdf11 mutant zebrafish showed craniofacial abnormalities and body segmentation defects that matched some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) allele whereas the missense variants are partial LOF variants.
PMID 31215115: In 5 affected members over 3 generations of a family segregating vertebral hypersegmentation and orofacial anomalies, Cox et al. (2019) identified heterozygosity for a missense mutation in the GDF11 gene (R298Q) that was not found in unaffected family members or in public variant databases. Functional analysis demonstrated that the R298Q substitution prevents cleavage to the active form of the protein, resulting in loss of function.
Sources: LiteratureCreated: 11 Oct 2021, 9:58 a.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes
Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122
Publications
Tag Q4_21_rating was removed from gene: GDF11.
Source NHS GMS was added to GDF11. Source Expert Review Green was added to GDF11. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: gdf11 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: GDF11 were changed from Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122 to Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM:619122
Publications for gene: GDF11 were set to 31215115; 34113007
Tag Q4_21_rating tag was added to gene: GDF11.
gene: GDF11 was added gene: GDF11 was added to Clefting. Sources: Literature Mode of inheritance for gene: GDF11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GDF11 were set to 31215115; 34113007 Phenotypes for gene: GDF11 were set to Vertebral hypersegmentation and orofacial anomalies (VHO), OMIM #619122 Review for gene: GDF11 was set to GREEN