Fetal anomalies
Gene: EN1

EN1 (engrailed homeobox 1)
EnsemblGeneIds (GRCh38): ENSG00000163064
EnsemblGeneIds (GRCh37): ENSG00000163064
OMIM: 131290, Gene2Phenotype
EN1 is in 3 panels

3 reviews

Achchuthan Shanmugasundram (Genomics England Curator)

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.
Created: 26 Sep 2024, 11:09 a.m. | Last Modified: 26 Sep 2024, 11:09 a.m.

Panel Version: 4.192

This gene and phenotype were reviewed during meetings between November 2023 & July 2024. The meetings included representatives of the North Thames and Central & South R21 testing GLHs and from the R21 Clinical Oversight Group. Clinical review and curation was performed by Natalie Chandler, Alison Male and Lyn Chitty (North Thames GLH), Stephanie Allen, Natalie Bibb, Esther Kinning and Denise Williams (Central & South GLH) and Natalie Canham, Anna De Burca and Samantha Doyle R21 Clinical Oversight Group. Outcome of review: Confirmed that the phenotype is fetally relevant, support adding to the Fetal anomalies panel as a Green gene.
Created: 29 Aug 2024, 8:33 p.m. | Last Modified: 30 Aug 2024, 9:51 a.m.

Panel Version: 4.55

This review was provided by Alison Male from North Thames GLH: Would expect to see prenatally. Enough evidence for Green
Created: 29 Aug 2024, 8:07 p.m. | Last Modified: 29 Aug 2024, 8:07 p.m.

Panel Version: 4.35

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
ENDOVE syndrome, limb-brain type, OMIM:619218

Publications

33568816

Created: 29 Aug 2024, 8:07 p.m.
Last Modified: 30 Aug 2024, 9:51 a.m.
Panel version: 4.192

Eleanor Williams (Genomics England Curator)

This gene was copied from the Skeletal dysplasia panel to the Fetal anomalies panel. The Genomics England clinical team have agreed that Fetal anomalies is an appropriate panel for this gene and the rating should currently be amber.
Created: 26 Jul 2023, 2:01 p.m. | Last Modified: 26 Jul 2023, 2:01 p.m.

Panel Version: 3.92

The Genomics England clinical team confirm that the rating of this gene should currently be amber based on 1 case and a mouse model.
Created: 26 Jul 2023, 1:18 p.m. | Last Modified: 26 Jul 2023, 1:18 p.m.

Panel Version: 4.10

Comment on list classification: Promoting from grey to amber. One patient with a loss of function variant in this gene and a skeletal phenotype reported, plus mouse model with this gene knocked out also shows a skeletal phenotype.

A further 3 patients with 27 and 63Kb deletions 300Kb upstream of this gene also show a skeletal phenotype and this appears to be due to ablation of a long non-coding RNA loci (in mice). However, at this distance it is unlikely to be detected by the Genomics England rare disease pipeline as being associated with EN1, and there are currently no regions on Skeletal dysplasia panel covering that area of chr 2. Therefore, at the present time this gene should be rated amber, following confirmation by the clinical team.
Created: 30 May 2023, 12:10 a.m. | Last Modified: 30 May 2023, 12:10 a.m.

Panel Version: 4.7

As reviewer Zornitza Stark reports there are have been 4 cases reported in PMID:33568816 Allou et al 2021, of patients with a severe congenital limb malformation (severe shortening and deformation of the legs and feet, 3/4 syndactyly of the hands, as well as the presence of nails on the palmar side of fingers IV and V). Patients 1 and 2 were found to have identical homozygous deletions (27-kb) on chromosome 2, patient 3 was homozygous for a 63-kb deletion and a 2.5-kb insertion in the same region. The minimal critical region is located ~300 kb upstream of engrailed-1 (EN1), a gene critical for dorsal–ventral patterning in the limb. Genome-wide transcriptome analysis in the developing mouse limb found a four-exon-long non-coding transcript within the deleted region, which they named Maenli. The authors suggest that the deletions cause altered expression of EN1.

Patient 4 was found to have a biallelic loss-of-function mutation (NM_001426.3: c.317dupT; p.Ile107HisfsTer39) in EN1 and had a limb phenotype similar to those in patients 1–3 and, in addition, a severe neurological condition characterized by spasticity, seizures and complete aplasia of the cerebellum.

They generated mice with the orthologous minimal critical region deleted and found they showed a strong limb malformation phenotype.

PMID: 7925010 - Wurst et al 1994 - report that En1-/- mice died shortly after birth and exhibited multiple developmental defects including cerebellar hypoplasia disruption of patterning of the forelimb paws and sternum.
Created: 29 May 2023, 11:51 p.m. | Last Modified: 29 May 2023, 11:51 p.m.

Panel Version: 4.6

Created: 29 May 2023, 11:51 p.m.
Last Modified: 29 May 2023, 11:51 p.m.
Copied from panel: Skeletal dysplasia v4.10

Zornitza Stark (Australian Genomics)

Green List (high evidence)

Three unrelated families reported (though two shown to be related by descent) with predominantly a skeletal phenotype comprising mesomelic shortening and deformation of the lower limbs due to severe hypoplasia of the tibia and fibula. This was accompanied by abnormalities of the digits of the hands and feet, with cutaneous and osseous syndactyly as well as dysplastic, missing, and/or volar nails. In addition, genitourinary anomalies were observed in some.

Homozygous deletions identified in all, with the minimal deleted region being a 27-kb interval (chr2: 118,561,492-118,589,320) located approximately 300 kb upstream of the EN1 gene.

Mouse model recapitulated the phenotype.

An additional fourth individual had cerebellar hypoplasia in addition to the skeletal phenotype, and a bi-allelic LoF variant.
Sources: Literature
Created: 5 Mar 2021, 6:44 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
ENDOVE syndrome, limb-only type, MIM# 619217; ENDOVE syndrome, limb-brain type, MIM# 619218

Publications

33568816

Variants in this GENE are reported as part of current diagnostic practice

Created: 5 Mar 2021, 6:44 a.m.

Copied from panel: Skeletal dysplasia v4.10

Details

Mode of Inheritance

BIALLELIC, autosomal or pseudoautosomal

Sources

Expert Review Green
NHS GMS
Literature

Phenotypes

ENDOVE syndrome, limb-brain type, OMIM:619218

OMIM

131290

Clinvar variants

Variants in EN1

Penetrance

None

Publications

33568816

Panels with this gene