Early onset or syndromic epilepsy

Gene: CRELD1

Green List (high evidence)

I cannot find any evidence that monoallelic variants in this gene are associated with neurological phenotypes including seizures, therefore suggest that inheritance is changed to biallelic only for this panel

Created: 16 Dec 2024, 12:50 p.m. | Last Modified: 16 Dec 2024, 12:50 p.m.

Panel Version: 7.13

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

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

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 1:13 p.m. | Last Modified: 6 May 2024, 9:18 p.m.

Panel Version: 5.6

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Green List (high evidence)

Comment on mode of inheritance: The mode of inheritance for CRELD1 on this panel should be changed from "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" to "BIALLELIC, autosomal or pseudoautosomal".

Created: 17 Dec 2024, 5:48 p.m. | Last Modified: 17 Dec 2024, 5:48 p.m.

Panel Version: 7.17

Comment on phenotypes: Monoallelic variants are associated with Atrioventricular septal defect, partial, with heterotaxy syndrome, OMIM:606217;{Atrioventricular septal defect, susceptibility to, 2}, OMIM:606217;atrioventricular septal defect, susceptibility to, 2, MONDO:0011650. However, this condition is not relevant to Early onset or syndromic epilepsy panel.

Created: 17 Dec 2024, 5:41 p.m. | Last Modified: 17 Dec 2024, 5:41 p.m.

Panel Version: 7.15

Biallelic CRELD1 variants have been associated with Jeffries-Lakhani neurodevelopmental syndrome (OMIM:620771) and it is a moderate G2P gene for CRELD1-related neurodevelopmental disorder with hypotonia and seizures. At least four CRELD1 variants have been reported in at least 14 patients from 10 unrelated families (PMID: 37947183).

Created: 17 Dec 2024, 5:38 p.m. | Last Modified: 17 Dec 2024, 5:38 p.m.

Panel Version: 7.14

Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.

Created: 28 Sep 2023, 9:06 a.m. | Last Modified: 28 Sep 2023, 9:06 a.m.

Panel Version: 4.102

Personal communication from Natalie Trump
There are now a total of 18 affected probands (14 families) with recessive variants in CRELD1 :

16 with a frameshift in trans with a missense variant

1 homozygous for a commonly recurrent missense variant (C192Y)

1 compound heterozygous for two missense variants (C192Y & A391P)

0 homozygous or compound het for putative null alleles

This data has been accepted for publication.

All 18 probands has epilepsy, hypotonia, speech delay and motor delay.

Created: 29 Aug 2023, 9:16 a.m. | Last Modified: 28 Sep 2023, 9:04 a.m.

Panel Version: 4.101

Not associated with a neurological phenotype in OMIM, Gen2Phen or MONDO. PMID: 32437232 reports a case with a seizure disorder who was compound heterozygous for CRELD1 variants (p.Q320Rfs*25, p.C192Y). Further unpublished CRELD1 variants associated with neurological disorders have been reported by Natalie Trump in her review in PanelApp.

Created: 24 Aug 2023, 10:31 a.m. | Last Modified: 24 Aug 2023, 10:31 a.m.

Panel Version: 4.94

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 37947183

Comment on phenotypes: Changed from "neurodevelopmental disorder;treatment resistant epileptic seizures;mild to severe developmental and cognitive delays;adrenal insufficiency;severe bilateral neural hearing loss;immature eye development;accuse respiratory distress and submucosal cleft palate" to "Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate" for Natalie Trump (Congenica) as the first option was entered by mistake.

Created: 3 Aug 2022, 2:16 p.m. | Last Modified: 3 Aug 2022, 2:16 p.m.

Panel Version: 2.558

Comment on mode of inheritance: Changed from "BOTH monoallelic and biallelic, autosomal or pseudoautosomal" to "BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal" for Natalie Trump (Congenica) as the first option was entered by mistake.

Created: 3 Aug 2022, 2:15 p.m. | Last Modified: 3 Aug 2022, 2:15 p.m.

Panel Version: 2.557

Green List (high evidence)

Heterozygous variants in CRELD1 are known to be associated with susceptibility to atrioventricular septal defect (AVSD), AVSD2 and AVSD associated with heterotaxy syndrome. Unaffected carriers have been reported suggesting reduced penetrance for this phenotype (OMIM 606217) .

Unpublished data has recently identified 9 unrelated families (including 3 families with 2 affected siblings each) with biallelic CRELD1 variants.

The most common feature in these children with biallelic CRELD1 variants is intractable seizures. Other features include global developmental delay and cognitive delay, treatment resistant epileptic seizures, adrenal insufficiency, severe bilateral neural hearing loss, immature eye development, acute respiratory distress and submucosal cleft palate.

All identified patients to-date are compound heterozygotes and each have one missense variant and one frameshift variant.
A recurrent missense variant (p.Cys192Tyr) has been identified in 8 individuals from 5 unrelated families. This missense change has been reported as a compound heterozygote with a frameshift variant a patient with seizures and global developmental delay (PMID: 32437232). This variant affects a cysteine residue that is predicted to form a disulphide bond in the protein which is important for protein folding and structural stability.
Two recurrent frameshift variants have also been identified:
- The p.Gln320ArgfsTer25 variant was found in 3 unrelated individuals (reported as compound heterozyogote in PMID: 32437232).
- The p.Ala377ThrfsTer7 variant was found in 5 individuals from 3 unrelated families.

CRELD1 encodes a member of a subfamily of epidermal growth factor-related proteins. CRELD1 plays a pivitol role in heart development and has also been shown to be an important gatekeeper of immune system homeostasis (PMID: 33169013).

There is one publication that reports a patient with seizures and global developmental delay with biallelic variants in CRELD1 (PMID: 32437232) but no other association between CRELD1 and brain function has been reported to date. Significantly, CRELD1 has high expression in human brain across different developmental stages.

There is no phenotype associated with biallelic CRELD1 variants in OMIM or G2P.

Created: 3 Aug 2022, 10:35 a.m. | Last Modified: 3 Aug 2022, 10:35 a.m.

Panel Version: 2.554

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Developmental epileptic encephalopathy; intractable seizures; global developmental delay and cognitive delay; treatment resistant epileptic seizures; adrenal insufficiency; severe bilateral neural hearing loss; immature eye development; acute respiratory distress; submucosal cleft palate

Publications

• PMID: 32437232

Mode of pathogenicity
Other