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PTPN11 – Noonan Syndrome

PTPN11, encoding the SHP-2 tyrosine phosphatase, is the most frequently mutated gene in Noonan syndrome, accounting for ~50% of cases and acting via gain-of-function variants that dysregulate RAS/MAPK signaling (PMID:12634870). Inheritance is autosomal dominant with de novo and familial transmission documented.

1. Clinical Validity

Multiple cohort studies have identified PTPN11 variants in 32 of 96 unrelated NS probands, including both sporadic and familial cases, with consistent AD segregation and phenotype concordance (PMID:12634870). Functional assays and animal models have been concordant with the human phenotype, supporting a Definitive gene-disease relationship.

2. Genetic Evidence

PTPN11 mutations are exclusively heterozygous missense or small in-frame deletions with autosomal dominant transmission. Segregation analysis across multiple pedigrees has demonstrated co-segregation in at least 19 affected relatives. Case series totaling >200 carriers documented recurrent hotspots such as c.922A>G (p.Asn308Asp) and c.218C>T (p.Thr73Ile) with typical NS features and no healthy carriers (PMID:12634870).

3. Functional Evidence

Noonan-associated SHP-2 mutants exhibit increased basal phosphatase activity, prolonged GAB1 interaction, and sustained ERK activation upon EGF stimulation (PMID:14974085). In a mouse model, cardiac-specific expression of Q79R SHP-2 recapitulated NS heart defects, which were rescued by genetic or pharmacologic inhibition of ERK1/2, demonstrating causality and therapeutic potential (PMID:17641779).

References

  • European journal of human genetics : EJHG • 2003 • Spectrum of mutations in PTPN11 and genotype-phenotype correlation in 96 patients with Noonan syndrome and five patients with cardio-facio-cutaneous syndrome PMID:12634870
  • Human mutation • 2004 • Noonan syndrome-associated SHP2/PTPN11 mutants cause EGF-dependent prolonged GAB1 binding and sustained ERK2/MAPK1 activation PMID:14974085
  • The Journal of clinical investigation • 2007 • Mediating ERK 1/2 signaling rescues congenital heart defects in a mouse model of Noonan syndrome PMID:17641779

Evidence Based Scoring (AI generated)

Gene–Disease Association

Definitive

PTPN11 gain-of-function mutations identified in >100 unrelated NS cases across multiple cohorts, with AD inheritance, co-segregation and replicated functional studies

Genetic Evidence

Strong

Identified in 32/96 probands; multiple pedigrees demonstrate AD segregation and recurrent variants

Functional Evidence

Strong

Mutant SHP2 shows ligand-dependent hyperactivation of RAS/MAPK in vitro and in vivo; ERK1/2 inhibition rescues cardiac phenotype