Multiple monogenic benign skin tumours

Gene: NOTCH3

Removed the Q4_21_expert_review and Q4_21_NHS_review tags from this gene, and added the watchlist tag as it has only enough evidence for Amber at the moment. If more evidence is found to support the gene-disease association then the eligibility criteria for the panel needs to be expanded before promoting the gene to green.

Created: 16 Mar 2022, 3:44 p.m. | Last Modified: 16 Mar 2022, 3:44 p.m.

Panel Version: 1.20

Comment on list classification: Promoting from grey to amber. 1 case plus functional studies supporting the role of the reported NOTCH3 variant in disease. Note the eligibility criteria for the clinical indication will need to be expanded before promoting to green.

Created: 24 Nov 2021, 6:27 p.m. | Last Modified: 25 Nov 2021, 4:48 p.m.

Panel Version: 1.18

Provisionally associated with ?Myofibromatosis, infantile 2 #615293 (AD) in OMIM which they state is characterized by the development of benign tumors in the skin, muscle, bone, and viscera.

PMID: 23731542 - Martignetti et al 2013 - In a family with Infantile myofibromatosis exome sequencing identified a heterozygous variant in NOTCH along with another candidate variant. By performing Sanger sequencing of 16 family members (9 affected and 7 unaffected) they found that only NOTCH3 mutation c.4556T>C (p.Leu1519Pro) segregated appropriately with affected status.

PMID: 33509954 - Wu et al 2021 - looked at the molecular consequences of the NOTCH3 L1519P mutation using HEK293 cells. The NOTCH3L1519P receptor generates enhanced downstream signaling in a ligand-independent manner, but is absent from the cell surface and accumulates in the endoplasmic reticulum instead. The protein with the variant upregulates PDGFRB expression in fibroblasts. This supports a functional link between Notch and PDGF dysregulation in Infantile myofibromatosis.

Created: 24 Nov 2021, 6:01 p.m. | Last Modified: 24 Nov 2021, 6:24 p.m.

Panel Version: 1.12

Publications

• 33509954
• 23731542

I don't know

Request to add PDGFRB and NOTCH3 to MMBST panel - phenotype appropriate, but may need to broaden eligibility criteria simultaneously.
Sources: Other

Created: 21 Oct 2021, 4:18 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
MYOFIBROMATOSIS, INFANTILE, 2

Publications

• 23731542