Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1.

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. 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. 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. Adding NF1 and SPRED1 to RASopathy panels can speed diagnosis and improve patient management, without significantly increasing the burden of inconclusive results. © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

Citation

Leora Witkowski, Mitchell W Dillon, Elissa Murphy, Matthew S Lebo, Heather Mason-Suares. Expanding the Noonan spectrum/RASopathy NGS panel: Benefits of adding NF1 and SPRED1. Molecular genetics & genomic medicine. 2020 Apr;8(4):e1180

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PMID: 32107864

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