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Noonan syndrome with multiple lentigines (NSML; formerly LEOPARD syndrome) is a rare autosomal-dominant RASopathy characterized by multiple lentigines, hypertrophic cardiomyopathy, ocular hypertelorism, sensorineural deafness, genital anomalies and growth retardation. Germline missense variants in PTPN11, encoding the SHP-2 tyrosine phosphatase, are found in ~85% of clinically confirmed NSML patients, establishing PTPN11 as the primary disease gene in this condition. Precise genotype–phenotype correlations distinguish NSML-specific substitutions (e.g., p.Tyr279Cys, p.Thr468Met) from those causing classic Noonan syndrome or leukemia, reflecting distinct biochemical impacts on SHP-2 function.
Genetic evidence for PTPN11-NSML association includes multiple independent case series comprising ~75 probands (PMID:12161596; PMID:24775816; PMID:26377839; PMID:19864201). Segregation of heterozygous PTPN11 variants with NSML phenotypes has been documented in at least 15 affected relatives across 5 families, including parent-offspring and multigenerational transmission. No significant phenotype appears in non-carriers, supporting a high penetrance for lentigines and cardiac manifestations.
The spectrum of PTPN11 variants in NSML is dominated by recurrent missense changes clustered in the phosphatase domain and SH2–PTP interface. The most frequent allele, c.836A>G (p.Tyr279Cys), accounts for >50% of LS cases and recurs worldwide (PMID:12161596; PMID:26377839). Other hotspots include c.1403C>T (p.Thr468Met) and c.1517A>C (p.Gln506Pro), each linked to characteristic cardiocutaneous features. These variants exhibit autosomal-dominant transmission and are absent from healthy population databases.
Functional assays reveal that NSML-associated PTPN11 mutations have a dominant-negative effect on SHP-2 catalytic activity and alter SH2-domain–mediated substrate interactions. In vitro phosphatase measurements show substantially reduced dephosphorylation of physiological substrates (e.g., parafibromin) for p.Tyr279Cys and p.Thr468Met (PMID:16358218). Structural and cellular studies confirm that LS mutants disrupt the closed-to-open allosteric switch of SHP-2, impairing signal homeostasis. Zebrafish and mouse models expressing LS alleles recapitulate cardiac laterality defects and myocardial abnormalities, further supporting a loss-of-function mechanism that paradoxically leads to aberrant MAPK signaling.
Although PTPN11 pathogenic variants explain most NSML cases, genetic heterogeneity exists: two kindreds without detectable PTPN11 variants demonstrate linkage exclusion, indicating alternative genes or cryptic variants in non-coding regions (PMID:15690106). No recurrent genotype–phenotype outliers have been reported among PTPN11-negative NSML families, underscoring the primacy of PTPN11 screening in molecular diagnosis.
Collectively, the convergence of robust genetic, segregation, and functional data fulfills ClinGen criteria for a Definitive gene-disease relationship. Identification of NSML-specific PTPN11 alleles enables precise risk assessment, family counseling and informs surveillance for hypertrophic cardiomyopathy. Targeted therapies that modulate SHP-2 conformational dynamics or downstream MAPK/Akt pathways hold promise for future personalized interventions.
Gene–Disease AssociationDefinitive~75 probands across multiple cohorts; segregation in >15 affected relatives across ≥5 families; concordant functional studies Genetic EvidenceStrongMultiple independent LS families with ~75 probands; reached ClinGen genetic cap Functional EvidenceModerateDominant-negative effect of LS‐associated SHP-2 mutants in biochemical assays; zebrafish and cell models recapitulate disease features |