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Early onset or syndromic epilepsy v1.191 | MACF1 | Rebecca Foulger Source Wessex and West Midlands GLH was added to MACF1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.190 | MACF1 | Rebecca Foulger Source NHS GMS was added to MACF1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.189 | MACF1 | Rebecca Foulger reviewed gene: MACF1: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.188 | MACF1 | Tracy Lester reviewed gene: MACF1: Rating: GREEN; Mode of pathogenicity: Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype -please provide details in the comments; Publications: 30471716; Phenotypes: cortical malformation; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v1.31 | MACF1 | Rebecca Foulger Phenotypes for gene: MACF1 were changed from Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia; Lissencephaly 9 with complex brainstem malformation, 618325 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1173 | MACF1 | Sarah Leigh Marked gene: MACF1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1173 | MACF1 | Sarah Leigh Added comment: Comment when marking as ready: Not associated with phenotype in OMIM (last updated for this gene 05/17/2011) or in Gen2Phen. At least 7 variants reported in unrelated cases with intellectual disability, seizures, lissencephalyand brainstem dysplasia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1173 | MACF1 | Sarah Leigh Gene: macf1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1173 | MACF1 | Sarah Leigh Added comment: Comment on mode of inheritance: Authors of PMID 30471716 suggest that a gain of function or dominant negative mode of action as truncating variant are reported in EXAC | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1173 | MACF1 | Sarah Leigh Mode of inheritance for gene: MACF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1172 | MACF1 | Sarah Leigh Publications for gene: MACF1 were set to doi.org/10.1016/j.ajhg.2018.10.019 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1171 | MACF1 | Sarah Leigh Classified gene: MACF1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1171 | MACF1 | Sarah Leigh Gene: macf1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1170 | MACF1 | Sarah Leigh Mode of inheritance for gene: MACF1 was changed from MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1169 | MACF1 | Sarah Leigh Publications for gene: MACF1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Early onset or syndromic epilepsy v0.1095 | MACF1 |
Konstantinos Varvagiannis gene: MACF1 was added gene: MACF1 was added to Genetic epilepsy syndromes. Sources: Literature,Expert Review Mode of inheritance for gene: MACF1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: MACF1 were set to Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia Penetrance for gene: MACF1 were set to unknown Mode of pathogenicity for gene: MACF1 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: MACF1 was set to GREEN Added comment: Dobyns et al. (doi.org/10.1016/j.ajhg.2018.10.019) report on 9 individuals (all unrelated appart from a pair of monozygotic twins) with de novo variants in MACF1. All patients presented lissencephaly and brainstem hypoplasia with associated intellectual disability (9/9) and seizures (9/9). Seven of these individuals had de novo missense variants within the GAR domain and an eighth had a deletion of several exons also spanning this domain and leading to an in-frame deletion. A further ninth patient had a de novo missense variant in the spectrin repeat domain and was found to have similar features although the brainstem dysplasia was rather subtle. 5 missense variants (4 of which in the GAR domain) and an intragenic deletion are reported in total. The variants in the GAR domain were predicted to have important effect in the zinc-binding pocket. The spectrin repeat (SR4) is thought to have an important role for the function of MACF1 and further to neuronal migration. Knockdown of Macf1 in mice has been shown to result in developmental defects similar to the human malformation. The authors note that several high-confidence loss-of-function mutations are listed in ExAC and as a result this type of variants could be non-pathogenic (or lead to neurodevelopmental disorders with reduced penetrance). Still MACF1 has a pLI of 1.0. As for the missense variants, the authors suggest either a gain-of-function or dominant negative mechanism. Caution should be taken when interpreting variants as the ENST00000372915.7 (or MACF1-204) transcript is used for the predicted protein changes, although ENST00000361689.6 or MACF1-203 (corresponding to NM_012090.5) has also been used in some tables or figures. As a result, this gene can be considered for inclusion in this panel probably as green. Sources: Literature, Expert Review |