NF1 – Neurofibromatosis Type 1

Neurofibromatosis Type 1 (MONDO:0018975) is an autosomal dominant multisystem disorder caused by pathogenic variants in the NF1 gene (HGNC:7765). Clinically, NF1 manifests with café-au-lait macules, axillary freckling, Lisch nodules, cutaneous and plexiform neurofibromas, optic pathway gliomas, and skeletal dysplasias.

1. Clinical Validity

Overall association is classified as Definitive, based on:

• Over 1,000 unrelated probands with diverse NF1 variants across multiple cohorts.
• Familial segregation in multiple kindreds, including 4 additional affected relatives for the exon 25 missense variant (c.4337T>C (p.Leu1446Pro)) (PMID:10220149).
• Concordant functional data demonstrating loss of Ras-GAP activity.

2. Genetic Evidence

Inheritance is autosomal dominant with complete penetrance by adulthood. Segregation analysis of the GAP-region mutation c.4337T>C (p.Leu1446Pro) showed co-segregation in 4 affected family members (PMID:10220149). Case series identified recurrent truncating and splice-site variants, including the c.6855C>A (p.Tyr2285Ter) mutation in exon 37 in multiple tissues of affected patients (PMID:10494088). Multi-patient studies documented 13 distinct truncating mutations in 14 individuals, distributed across the gene without clustering (PMID:7655472).

3. Variant Spectrum

Over 500 unique NF1 variants have been reported, encompassing nonsense, frameshift, splice-site, and missense changes. Truncating alleles predominate, while recurrent CpG transitions (e.g., c.1087C>T (p.Arg363Ter)) and founder deletions are observed. The chosen representative variant is c.6855C>A (p.Tyr2285Ter), a recurrent nonsense change leading to premature termination.

4. Functional Evidence

Neurofibromin contains a GAP-related domain (GRD) homologous to yeast IRA proteins. The GRD of NF1 stimulates Ras GTPase activity, rescuing the heat-shock phenotype of ira1/ira2 mutants in yeast and markedly increasing GTP hydrolysis of Ras in vitro (PMID:2121369). Absence of functional neurofibromin in knockout mice recapitulates key NF1 features, supporting a haploinsufficiency mechanism.

5. Integration & Clinical Utility

Germline NF1 variants abrogate neurofibromin’s negative regulation of Ras signaling, driving tumorigenesis and developmental anomalies. The breadth of genetic findings exceeds the genetic evidence scoring cap but underpins well-established genotype-phenotype correlations. Key take-home: NF1 genetic testing is essential for definitive diagnosis, risk stratification, and guiding surveillance for NF1-associated complications.

References

• Human molecular genetics • 1995 • Distribution of 13 truncating mutations in the neurofibromatosis 1 gene. PMID:7655472
• Human mutation • 1999 • A novel mutation L1425P in the GAP-region of the NF1 gene detected by temperature gradient gel electrophoresis (TGGE). PMID:10220149
• Cell • 1990 • The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae. PMID:2121369
• American journal of medical genetics • 1999 • Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). PMID:10494088

Evidence Based Scoring (AI generated)