Early onset or syndromic epilepsy

Region: ISCA-37448-Loss

15q11.2 recurrent region (BP1-BP2) (includes NIPA1) Loss

Green List (high evidence)

The rating of this region has been updated to Green following NHS Genomic Medicine Service approval.

Created: 17 Mar 2026, 3:54 p.m. | Last Modified: 17 Mar 2026, 3:54 p.m.

Panel Version: 8.147

Comment on list classification: This region has Sufficient Evidence for Haploinsufficiency in ClinGen and should be promoted to Green at the next GMS panel update.

Panel inclusion has been reviewed and approved by the Genomics England Clinical team.

Created: 12 Nov 2025, 3:56 p.m. | Last Modified: 12 Nov 2025, 3:56 p.m.

Panel Version: 8.63

https://search.clinicalgenome.org/kb/gene-dosage/region/ISCA-37448

ClinGen review (Last Evaluated:04/12/2021): Deletion of the 15q11.2 (BP1-BP2) region has historically been reported in association with highly variable clinical phenotypes. Features observed in carrier patients referred for clinical genome wide copy number testing have been relatively nonspecific, including developmental delay/intellectual disability (DD/ID), epilepsy, autism spectrum disorder (ASD), schizophrenia, congenital heart disease (CHD), and variable dysmorphic features, which are also generally common in this patient population. This deletion has been shown to be enriched in the clinical population across multiple case-control studies. However, in the clinical setting, it is often inherited from unaffected carriers, and the deletion is also observed in the general population at a relatively high frequency (0.14 - 0.39%; PMID: 25217958, 30767844). The expression of any phenotype associated with this deletion has been estimated to be between 8-10%. This has led to a high level of variability in how this region is reported clinically.

Large cohort studies involving 15q11.2 (BP1-BP2) deletion carriers from the general population have consistently demonstrated that individuals who carry this deletion perform worse on cognitive function tests than non-carrier individuals. This difference has been reported to be significant, but with a mild effect size, consistent with the deletion being a susceptibility locus for neurodevelopmental phenotypes. Additionally, these studies suggest ascertainment bias may be responsible for the association of this deletion with the more severe clinical phenotypes (ID, epilepsy, ASD and CHD) observed in cases identified through clinical testing.

Collectively, the current literature is consistent with the 15q11.2 (BP1-BP2) deletion having a subclinical, but measurable, effect on neurocognitive function. Other reported clinical associations are not conclusively established, and likely reflect a bias of ascertainment. Therefore, there is sufficient evidence for haploinsufficiency of this region.


Additional comments from Genomics England Clinical team: There are significant issues with penetrance for these but I understand the NHS would still report them in the context of disease (https://www.acgs.uk.com/media/12443/uk-practice-guidelines-for-variant-classification-v1-2023.pdf) Therefore, agree with the recommendations.
Sources: ClinGen

Created: 12 Nov 2025, 3:54 p.m. | Last Modified: 12 Nov 2025, 3:55 p.m.

Panel Version: 8.62

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

Publications

• 31451536
• 24352232
• 30767844
• 31665216