Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only

The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for H...

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Published inEBioMedicine Vol. 7; no. C; pp. 212 - 220
Main Authors Evans, D.G., Bowers, N., Burkitt-Wright, E., Miles, E., Garg, S., Scott-Kitching, V., Penman-Splitt, M., Dobbie, A., Howard, E., Ealing, J., Vassalo, G., Wallace, A.J., Newman, W., Huson, S.M.
Format Journal Article
LanguageEnglish
Published Netherlands Elsevier B.V 01.05.2016
Elsevier
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Summary:The detection rate for identifying the underlying mutation in neurocutaneous syndromes is affected by the sensitivity of the mutation test and the heterogeneity of the disease based on the diagnostic criteria. Neurofibromatosis type (NF1) has been defined for 29years by the National Institutes for Health (NIH) criteria which include ≥6 Café au Lait macules (CAL) as a defining criterion. The discovery of SPRED1 as a cause of Legius syndrome which is manifested by CAL, freckling and learning difficulties has introduced substantial heterogeneity to the NIH criteria. We have defined the sensitivity of comprehensive RNA analysis on blood of presumed NF1 patients meeting NIH criteria with at least one nonpigmentary criterion and determined the proportion of children with ≥6 CAL and no family history that has an NF1 or SPRED1 genetic variant. RNA analysis was carried out from 04/2009–12/2015 on 361 NF1 patients. A presumed causative NF1 mutation was found in 166/171 (97.08%–95% CI 94.56–99.6%) of familial cases and 182/190 (95.8%–95% CI 92.93–98.65%) sporadic de novo cases. Two of thirteen (15%) mutation negative individuals had dysembryoplastic neuroepithelial tumour (DNET) compared to 2/348 (0.6%) with an NF1 variant (p=0.007). No SPRED1 variants were found in the thirteen individuals with no NF1 variant. Of seventy-one individuals with ≥6 CAL and no non-pigmentary criterion aged 0–20years, 47 (66.2%) had an NF1 variant six (8.5%) a SPRED1 variant and 18 (25.3%) no disease causing variant. Using the 95.8% detection rate the likelihood of a child with ≥6 CAL having constitutional NF1 drops from 2/3 to 1/9 after negative RNA analysis. RNA analysis in individuals with presumed NF1 has high sensitivity and includes a small subset with DNET without an NF1 variant. Furthermore negative analysis for NF1/SPRED1 provides strong reassurance to children with ≥6 CAL that they are unlikely to have NF1. •RNA testing for NF1 mutations has very high sensitivity (c.96%) and is significantly more sensitive than DNA testing.•Mosaicism is not a major feature in those with classical NF1.•Around two thirds of children with just 6 or more café au lait spots have NF1, 8% Legius syndrome.•Patients with normal RNA testing who meet NF1 criteria but also have a DNET may have a fault in a yet to be identified gene. Identifying the underlying genetic mutation is of benefit to patients and their families as it clarifies the diagnosis, can give information on the likely disease course and allow predictive testing in pregnancy and early childhood. The present study has shown that testing of blood RNA has very high sensitivity (96%) and allows substantial reassurance to parents whose children have multiple Café au lait birthmarks that they are unlikely to have the poorer outcomes of NF1 if they test negative. Furthermore the study suggests that a different mechanism may underlie the association of NF1 features and a rare benign brain tumour called DNET.
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Northern UK NF1 research Network: Manchester NF1 service: Sue Huson, D. Gareth Evans, John Ealing, Elizabeth Howard, Emma Burkett-Wright, Eileen Hupton, Sonia Patel, Judith Eelloo, Liz Rowles, Maria Gault, Grace Vasallo & Siobhan West. Yorkshire Regional NF1 service: Angus Dobbie, Ruth Drimer, Saghira Malik; Alderhey NF1 clinic: Zahabiyah Bassi & Jamuna Acharya; Edinburgh Genetic Service: Wayne Lam; Sheffield NF1 clinic: Neil Harrower, Oliver Quarrell, Alyson Bradbury Diane Johnson; Newcastle NF1 service: Miranda Splitt, Susan Musson, Rachel Jones, Helen Bethell, Catherine Prem, Alex Henderson. Sunderland NF1 clinic: Karen Horridge. Warrington NF1 clinic: Shaheena Anjum. Wirral University Hospitals NF1 clinic: Christine Steiger.
ISSN:2352-3964
2352-3964
DOI:10.1016/j.ebiom.2016.04.005