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| Paediatric disorders - additional genes v4.3 | NOTCH3 |
Achchuthan Shanmugasundram Tag Q4_23_promote_green was removed from gene: NOTCH3. Tag Q4_23_expert_review was removed from gene: NOTCH3. |
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| Paediatric disorders - additional genes v4.3 | NOTCH3 | Sarah Leigh reviewed gene: NOTCH3: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v4.2 | NOTCH3 |
Achchuthan Shanmugasundram Source Expert Review Green was added to NOTCH3. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Paediatric disorders - additional genes v3.9 | NOTCH3 | Arina Puzriakova Classified gene: NOTCH3 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v3.9 | NOTCH3 | Arina Puzriakova Gene: notch3 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric disorders - additional genes v3.8 | NOTCH3 |
Arina Puzriakova gene: NOTCH3 was added gene: NOTCH3 was added to Paediatric disorders - additional genes. Sources: NHS GMS Q4_23_promote_green, Q4_23_expert_review tags were added to gene: NOTCH3. Mode of inheritance for gene: NOTCH3 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: NOTCH3 were set to 25394726 Phenotypes for gene: NOTCH3 were set to Lateral meningocele syndrome, OMIM:130720 Mode of pathogenicity for gene: NOTCH3 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: NOTCH3 was set to GREEN Added comment: Monoallelic variants in the NOTCH3 gene are associated with multiple phenotypes including CADASIL (MIM# 125310), Lateral Meningocele syndrome (MIM# 130720), and Myofibromatosis (MIM# 615293). Currently, CADASIL and myofibromatosis phenotypes are covered by several PanelApp panels; however, Lateral Meningocele syndrome is not - there is enough evidence to support inclusion of this gene-disease association on a diagnostic-grade panel. At least 5 unrelated de novo cases have been reported in literature (PMID: 25394726). All variants are truncating and cluster in the last exon of NOTCH3. Truncated proteins are predicted to cause increased notch signalling. An additional case was identified in Genomics England's Clinical Variant Archive (CVA) dataset via the Diagnostic Discovery initiative. The participant was recruited with Lateral Meningocele syndrome (inclusive of hypertelorism, high palate, dural ectasia, high pitched voice) and a diagnostically reported variant in the last exon of this gene was returned, lending further support to adding this gene to the panel. R27 appears to be the most phenotypically relevant panel for detecting Lateral Meningocele syndrome; however, the possibility of incidental findings of CADASIL needs to be considered. Both phenotypes are caused by GoF variants but those associated with CADASIL are located in exons 2-24 whereas variants in Lateral Meningocele found in exon 33 (last exon). Given the risk of incidental findings without a mechanism to delineate the types of variants that are prioritised via each panel, the best route for inclusion of Lateral Meningocele syndrome in PanelApp will be flagged for further NHSE expert discussion at the next GMS panel update release. Sources: NHS GMS |
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