MAP2K1 – Noonan syndrome with multiple lentigines

Noonan syndrome with multiple lentigines (NSML) is an autosomal dominant RASopathy predominantly linked to PTPN11, RAF1, and BRAF. A single unrelated proband, a 13-year-old Japanese boy presenting with multiple lentigines, sensorineural hearing impairment, and precocious puberty, was found to harbor a novel heterozygous missense variant in MAP2K1: c.305A>G (p.Glu102Gly) ([PMID:25423878]). No additional segregation of this variant has been documented. The variant lies within the negative regulatory region of MEK1, implicating a potential gain-of-function mechanism akin to other pathogenic MAP2K1 alleles described in RASopathies, although no functional data specific to p.Glu102Gly are available. There are no conflicting reports disputing this association. Collectively, the genetic evidence remains limited but supports inclusion of MAP2K1 in NSML diagnostic panels.

Key Take-home: MAP2K1 c.305A>G (p.Glu102Gly) expands the molecular spectrum of NSML and should be considered in genetic testing workflows.

References

• American journal of medical genetics. Part A • 2015 • A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines PMID:25423878

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