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Neurofibromatosis-Noonan syndrome (NFNS) is a rare RASopathy combining features of neurofibromatosis type 1 (NF1) and Noonan syndrome (MONDO:0011035). Genetic testing in three unrelated families (eight affected individuals) identified heterozygous NF1 variants (c.5425C>T (p.Ser1809Arg), c.6789_6792delTTAC (p.Tyr2264Ter), and c.2991-1G>A) as causative, with no pathogenic variants detected in alternative RAS-MAPK genes including MAP2K2 (PMID:24357598).
Despite comprehensive screening of MAP2K2 in NFNS cohorts, no MEK2 missense, frameshift, or splice-site mutations were reported, and segregation analysis revealed zero MAP2K2‐related cases. Functional studies of MAP2K2 in other contexts demonstrate its role downstream of RAF in MAPK signaling, but no experimental or clinical evidence implicates MEK2 in NFNS pathogenesis.
Key Take-home: There is currently no genetic or functional evidence supporting MAP2K2 as a disease gene for Neurofibromatosis-Noonan syndrome; NF1 remains the sole driver.
Gene–Disease AssociationRefutedNo MAP2K2 variants identified in NFNS families; all causative variants were in NF1 ([PMID:24357598]) Genetic EvidenceRefuted0 probands with MAP2K2 variants; comprehensive screening in three families yielded no pathogenic alleles Functional EvidenceRefutedNo experimental data linking MAP2K2 dysfunction to NFNS phenotype |