Intellectual disabilityGene: CYFIP2
Comment on list classification: Expert review by Konstantinos Varvagiannis on CYFIP2.
Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants, pedigree details shown to support MOI. One child experienced developmental delay before the onset of seizures.
Peng et al. (PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence.
Zweier et al. (PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants.
Of the 17 cases identified, 9 variants affected Arg87 residue. All individuals are reported to have DD/ID.
CYFIP2 is in OMIM as Epileptic encephalopathy, early infantile, 65 with clinical symptoms of profound DD, but not in G2P.
Overall sufficient (>3) unrelated cases of DD in patients with CYFIP2 variants, for inclusion on ID panel.
Created: 16 May 2019, 2 p.m. | Last Modified: 3 Jul 2019, 9:50 a.m.
Panel Version: 0.196
Heterozygous pathogenic variants in CYFIP2 cause Epileptic encephalopathy, early infantile, 65 (MIM 618008)
[Apologies for any eventual mistakes esp.as for the functional evidence]:
Nakashima et al. (2018 - PMID: 29534297) report on 4 unrelated individuals with early-onset epileptic encephalopathy due to de novo missense CYFIP2 variants.
The phenotype consisted of early-onset intractable seizures (diagnosis of West syndrome in 2, Ohtahara syndrome in further individuals) with hypotonia (3/4), DD/ID (4/4) and microcephaly (3/4).
All variants affected Arg87 residue (NM_001037333.2:c.259C>T or p.Arg87Cys in 2 individuals, the 2 other subjects harbored Arg87Leu and Arg87Pro respectively).
CYFIP2 encodes the cytoplasmic FMRP interacting protein 2. CYFIP2 (similar to CYFIP1) is a component of the WAVE regulatory complex (WRC) which has been shown to play a role in actin remodeling, axon elongation, dendritic morphogenesis and synaptic plasticity (several PMIDs cited).
In the inactive state of the WRC complex, CYFIP2 binds to the VCA domain of WAVE. GTP-bound Rac1 (GTPase) leads to release of the VCA domain from CYFIP2 which allows binding of this domain to the Arp2/3 complex (active WRC state) and in turn stimulates actin polymerization and lamellipodia formation.
Using lymphoblastoid cell lines from affected individuals and healthy controls and CYFIP2 expression was evaluated by Western Blot and was found to be similar between the 2 groups.
Additional studies suggested weaker binding of the WAVE1 VCA domain to mutant CYFIP2 compared to WT CYFIP2 (upon transfection of HEK293T cells). This could possibly favor activation of WRC (/the WAVE signalling pathway).
As a result a gain-of-function effect on the WAVE signalling pathway is suggested as a possible mechanism.
Using B16F1 mouse melanoma cells lamellipodia formation (process in which CYFIP2 has previously been implicated) was not shown to be impaired in the case of mutant CYFIP2. However aberrant accumulation of F-actin (and co-localization with mutant CYFIP2) was observed in the present study.
Only large 5q deletions spanning CYFIP2 (and several other genes) have been described to date.
Cyfip2 heterozygous knockout in mice results in abnormal behavior and memory loss. WAVE activity was enhanced (despite reduced WAVE protein production). Homozygous Cyfip2 loss is lethal (PMIDs cited by the authors: 25432536, 27524794). Impaired axonal growth, guidance and branching is noted in Drosophila mutants (CYFIP1/2 ortholog) (PMID cited: 12818175). The authors comment that Cyfip2 (nev) mutant zebrafish show a similar phenotype to mutant flies (PMID cited: 20537992).
Peng et al. (2018 - PMID: 29667327) in a study of 56 Chinese families with West Syndrome (epileptic/infantile spasms, hypsarrhytmia and ID) identified 1 individual with the Arg87Cys CYFIP2 variant as a de novo occurrence.
Zweier et al. (2019 - DDD study among the co-authors - PMID: 30664714) report on 12 unrelated subjects with heterozygous pathogenic de novo CYFIP2 variants.
The common phenotype consisted of tone abnormalities (12/12), DD/ID (12/12) and seizures (12/12 though a single individual had experienced a single episode of febrile seizure). Absolute or relative microcephaly and/or additional features were also noted in several individuals.
7 missense variants (4 occurrences of the Arg87Cys variant) as well as splice variant (shown to lead to exon skipping) are reported, as de novo events in these individuals. The splice variant was expected to escape NMD producing a truncating protein.
Although the variants are distantly located in the primary structure, spatial clustering (in the tertiary structure) is suggested by in silico modelling (all in proximity at the CYFIP2-WAVE1 interface).
CYFIP2 appears to be intolerant to both missense and LoF variants (Z-score of 6.15 and pLI of 1 respectively in ExAC).
The authors comment that haploinsufficiency as a mechanism is rather unlikely given the absence of small CNVs or variants predicted to lead to NMD. Again, a gain-of-function effect of these variants on WAVE activation (partial-loss-of function in terms of WRC stabilization and/or conformation of the VCA region in the inactive state) is proposed.
CYFIP2 is not associated with any phenotype in G2P.
The gene is included in gene panels for intellectual disability offered by some diagnostic laboratories (eg. participants in these studies).
As a result this gene could be considered for inclusion in this panel as green.
Created: 25 Jan 2019, 8 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Epileptic encephalopathy, early infantile 65, 618008
Variants in this GENE are reported as part of current diagnostic practice
Source Expert Review Green was added to CYFIP2. Source Expert Review was added to CYFIP2. Added phenotypes Epileptic encephalopathy, early infantile, 65, 618008 for gene: CYFIP2 Publications for gene CYFIP2 were changed from 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 to 12818175; 30664714; 20537992; 29534297; 25432536; 27524794; 29667327 Rating Changed from No List (delete) to Green List (high evidence)
gene: CYFIP2 was added gene: CYFIP2 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: CYFIP2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: CYFIP2 were set to 29534297; 29667327; 30664714; 25432536; 27524794; 12818175; 20537992 Phenotypes for gene: CYFIP2 were set to Epileptic encephalopathy, early infantile 65, 618008 Penetrance for gene: CYFIP2 were set to unknown Review for gene: CYFIP2 was set to GREEN gene: CYFIP2 was marked as current diagnostic