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

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.

Neurofibromatosis type 1: Expanded variant spectrum with multiplex ligation‐dependent probe amplification and genotype–phenotype correlation in 138 Turkish patients

“…The absence of neurofibromas in these patients can be explained by their young age, as previously reported by Witkowski et al. (2020). Regarding malignancies, optic and hypothalamic glioma detected in two unrelated patients suggest a higher incidence of malignancies in the patient group with large deletions (2/7).…”

Phenotype–genotype analysis of 242 individuals with RASopathies: 18‐year experience of a tertiary center in Brazil

“…These cases illustrate that in NFNS some individuals did not fulfill clinical criteria either for NF1 or NS, with variable expressivity, even within familial cases. Thus, NF1 should be included in the molecular evaluation of individuals with a NS gestalt and pigmented skin lesions (café‐au‐lait spots) (Witkowski, Dillon, Murphy, Lebo, & Mason‐Suares, 2020). The individual with a microdeletion encompassing NF1 presented unusual diffuse cervical vertebral meningoceles (Figures 4 and S1j).…”

Phenotypic and genetic characterization of novel variant in the NF1 gene underlying neurofibromatosis type 1 in five Chinese families

“…All variants detected from families were confirmed by Sanger sequencing (Figure 1B), and the spectrum of these variants was indicated in NF1 protein domains (Figure 1C), including 3 missense variants (NM_000267.3: c.1466A>G, p.Tyr489-Cys; c.730G>A, p.Glu244Lys; c.6056C>T, p.Ser2019Phe), a small duplication (c.2033dup, p.Ile679Aspfs*21), and a small deletion (c.4054_4058del, p.Ser1352Leufs*20). Two known missense variants (c.1466A>G, p.Tyr489Cys; c.6056C>T, p.Ser2019Phe) and the duplication (c.2033dup, p.Ile679Aspfs*21) were reported in HGMD and interpreted as pathogenic in the ClinVar database (Witkowski et al, 2020). Missense variant (c.6056C>T, p.Ser2019Phe) has been reported in NF1 patients from the Netherlands (van Minkelen et al, 2014), and this is the first time to report it among Chinese population.…”