Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1. Issue 4 (27th February 2020)

• Record Type: Journal Article
• Authors: Witkowski, Leora; Dillon, Mitchell W.; Murphy, Elissa; S Lebo, Matthew; Mason‐Suares, Heather
• Is Part Of: Molecular genetics & genomic medicine. Volume 8:Issue 4(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-27
• Subjects: Legius syndrome -- Neurofibromatosis type 1 -- Neurofibromatosis‐Noonan syndrome (NFNS) -- NF1 -- Noonan syndrome (NS) -- Noonan syndrome with multiple lentigines (NSML) -- RASopathy -- SPRED1 -- Watson syndrome; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1180
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: RASopathies are a group of disorders caused by disruptions to the RAS‒MAPK pathway. Despite being in the same pathway, Neurofibromatosis Type 1 (NF1) and Legius syndrome (LS) typically present with phenotypes distinct from Noonan spectrum disorders (NSDs). However, some NF1/LS individuals also exhibit NSD phenotypes, often referred to as Neurofibromatosis‐Noonan syndrome (NFNS), and may be mistakenly evaluated for NSDs, delaying diagnosis, and affecting patient management. Methods: A derivation cohort of 28 patients with a prior negative NSD panel and either NFNS or a suspicion of NSD and café‐au‐lait spots underwent NF1 and SPRED1 sequencing. To further determine the utility and burden of adding these genes, a validation cohort of 505 patients with a suspected RASopathy were tested on a 14‐gene RASopathy‐associated panel. Results: In the derivation cohort, six (21%) patients had disease‐causing NF1 or SPRED1 variants. In the validation cohort, 11 (2%) patients had disease‐causing variants and 15 (3%) had variants of uncertain significance in NF1 or SPRED1 . Of those with disease‐causing variants, 5/17 only had an NSD diagnosis. Conclusions: Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results. Abstract : Adding the NF1 and SPRED1 genes to Noonan spectrum disorder/RASopathy NGS gene panels modestly increases clinical diagnoses without significantly increasing the VUS burden. Since a diagnosis of NF1 or LS would change patient management, the NF1 and SPRED1 genes should be included on all to Noonan spectrum disorder/RASopathy NGS gene panels, including those used prenatally.