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Intellectual disability

Gene: MACF1

Green List (high evidence)
MACF1 (microtubule-actin crosslinking factor 1)
EnsemblGeneIds (GRCh38): ENSG00000127603
EnsemblGeneIds (GRCh37): ENSG00000127603
OMIM: 608271, Gene2Phenotype
MACF1 is in 7 panels

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by external expert and reviewed by curation team: Sufficient evidence has been provided by the external expert review for this gene to be rated green. The gene is associated with a phenotype on OMIM but not on Gene2Phenotype.
Created: 18 Feb 2019, noon
Created: 18 Feb 2019, noon

Panel version: 2.663

Konstantinos Varvagiannis (Other)

Green List (high evidence)

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 a 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
Created: 23 Nov 2018, 8:31 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Intellectual disability; Seizures; Lissencephaly; Brainstem dysplasia

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Created: 23 Nov 2018, 8:31 a.m.

Panel version: 2.555

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Green
Phenotypes
  • Intellectual disability
  • Seizures
  • Lissencephaly
  • Brainstem dysplasia
  • Lissencephaly 9 with complex brainstem malformation, 618325
OMIM
608271
Clinvar variants
Variants in MACF1
Penetrance
unknown
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

18 Feb 2019, Gel status: 3

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: macf1 has been classified as Green List (High Evidence).

18 Feb 2019, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MACF1 were set to 30471716

18 Feb 2019, Gel status: 0

Set publications

Ivone Leong (Genomics England Curator)

Publications for gene: MACF1 were set to

18 Feb 2019, Gel status: 0

Set Phenotypes

Ivone Leong (Genomics England Curator)

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

23 Nov 2018, Gel status: 0

Created, Added New Source, Set mode of inheritance, Set Phenotypes, Set penetrance, Set mode of pathogenicity

Konstantinos Varvagiannis (Other)

gene: MACF1 was added gene: MACF1 was added to Intellectual disability. 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