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Intellectual disability

Gene: EPHA7

Amber List (moderate evidence)
EPHA7 (EPH receptor A7)
EnsemblGeneIds (GRCh38): ENSG00000135333
EnsemblGeneIds (GRCh37): ENSG00000135333
OMIM: 602190, Gene2Phenotype
EPHA7 is in 1 panel

2 reviews

Ivone Leong (Genomics England Curator)

Comment on list classification: New gene added by Konstantinos Varvagiannis (Other). This gene is not associated with a phenotype in OMIM or Gene2Phenotype. This gene has been given an Amber rating based on expert review.
Created: 14 Jul 2021, 2 p.m. | Last Modified: 14 Jul 2021, 2 p.m.
Panel Version: 3.1192
Created: 14 Jul 2021, 2 p.m.
Last Modified: 14 Jul 2021, 2 p.m.
Panel version: 3.1192

Konstantinos Varvagiannis (Other)

I don't know

Lévy et al (2021 - PMID: 34176129) provide evidence that haploinssuficiency of EPHA7 results in a neurodevelopmental disorder.

The authors report on 12 individuals belonging to 9 unrelated families, all harboring with 6q microdeletions spanning EPHA7.

Overlapping features included DD (13/13), ID (10/10 - mild in most cases, individuals with larger CNVs/additional variants had more severe phenotype), speech delay and behavioral disorders. Variable other features incl. hypotonia (70%), non specific facial features, eye abnormalities (40%) and cardiac defects (25%).

The CNVs ranged from 152 kb to few Mb in size but in 4 subjects (P5-8) were only minimal, involving only EPHA7.

The 6q microdeletion included additional ID-related genes in at least one case (eg. ZNF292 in P12) while one subject (P4) harbored also a 7q11.23 Williams syndrome deletion.

Confirmation (e.g. with FISH or qPCR) and segregation analyses were performed. 9 out of 12 individuals had inherited the deletion (5 subjects paternal, 4 maternal), in 1 subject (P12) this occured de novo, while for 2 others inheritance was not specified. Most deletions were inherited from an unaffected parent (in 6/7 families), with unclear contribution in a further one.

Sequencing of an ID gene panel was performed for 5 subjects (P1-4 (sibs) and P9) and exome for 4 ones (P1,2,10,11). CNVs in all these subjects were not limited to EPHA7. These investigations did not reveal other variants responsible for the phenotype of these subjects.

EPHA7 encodes ephrin receptor A7. As the authors comment, ephrin receptors are the largest family of transmembrane receptor tyrosine kinases. These receptors interact with membrane bound ephrins and binding activates the tyrosine kinase activity of the receptor.

The authors discuss on previous studies suggesting an important role for EphA7 in brain development (modulation of cell-cell adhesion and repulsion, regulation of dendrite morphogenesis in early corticogenesis, role in dendritic spine formation later in development. EphA7 has also been proposed to drive neuronal maturation and synaptic function).

Haploinsufficiency for other ephrins or ephrin receptors has been implicated in other NDDs.

Finally the authors comment on a previous report of a de novo 2.16 Mb microdeletion spanning EPHA7 and another gene (TSG1). This deletion, reported by Traylor et al (2009 - PMID: 19664229) was identified in a 15-month old male with DD, microcephaly and dysmorphic features.

Overall Lévy et al promote incomplete penetrance and variable expressivity with haploinsufficiency of this gene being a risk factor for NDD. [The gene has also an %HI of 2.76% and a pLI of 1].

In DECIPHER there are 2 indivuals (DDD participants) with de novo missense variants and abnormality of the nervous system.

As a result this gene can be considered for inclusion in the ID panel with amber rating pending further evidence.
Sources: Literature
Created: 4 Jul 2021, 8:26 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality

Publications

Created: 4 Jul 2021, 8:26 p.m.

Panel version: 3.1154

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
Sources
  • Expert Review Amber
Phenotypes
  • Global developmental delay
  • Intellectual disability, MONDO:0001071
  • Delayed speech and language development
  • Behavioral abnormality
Tags
watchlist
OMIM
602190
Clinvar variants
Variants in EPHA7
Penetrance
Incomplete
Publications
Panels with this gene

History Filter Activity

14 Jul 2021, Gel status: 2

Added Tag

Ivone Leong (Genomics England Curator)

Tag watchlist tag was added to gene: EPHA7.

14 Jul 2021, Gel status: 2

Entity classified by Genomics England curator

Ivone Leong (Genomics England Curator)

Gene: epha7 has been classified as Amber List (Moderate Evidence).

14 Jul 2021, Gel status: 0

Set Phenotypes

Ivone Leong (Genomics England Curator)

Phenotypes for gene: EPHA7 were changed from Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality to Global developmental delay; Intellectual disability, MONDO:0001071; Delayed speech and language development; Behavioral abnormality

4 Jul 2021, Gel status: 0

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

Konstantinos Varvagiannis (Other)

gene: EPHA7 was added gene: EPHA7 was added to Intellectual disability. Sources: Literature Mode of inheritance for gene: EPHA7 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: EPHA7 were set to 34176129; 19664229 Phenotypes for gene: EPHA7 were set to Global developmental delay; Intellectual disability; Delayed speech and language development; Behavioral abnormality Penetrance for gene: EPHA7 were set to Incomplete Review for gene: EPHA7 was set to AMBER