ClinGen Dosage Sensitivity Curation Page

17q11.2 recurrent region (includes NF1)

  • Curation Status: Complete
  • id: ISCA-37431
  • Date last evaluated: 2016-05-28
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: (NC_000017.10) ()

Haploinsufficiency phenotype comments:

Deletions encompassing the gene neurofibromin (NF1), as well as other neighboring genes, account for 5-10% of patients with neurofibromatosis type I (NF1) and are mediated by flanking segmental duplications. Although patients with NF1 microdeletion syndrome show a variable clinical phenotype similar to patients with NF1 mutations, genotype-phenotype correlation studies have shown that microdeletion carriers may have larger numbers and earlier appearance of cutaneous neurofibromas, higher incidence and more severe cognitive abnormalities, facial dysmorphisms, and overgrowth. There is also variability in the size of NF1 microdeletions due to multiple segmental duplications in this region. Type 1 microdeletion is 1.4 Mb in size mediated by LCRs NF1 repeat(-REP) A and NF1 -REP C; type 2 microdeletion is 1.2 Mb in size with breakpoints within SUZ12 and SUZ12P; type3 is 1.0 MB in size mediated by NF1-REP B and NF1-REP C. Among NF1 microdeletion carriers, genotype-phenotype correlations have not yet been demonstrated.

Evidence for gain of function phenotype
PubMed ID Description
22241097 Moles et al (2012) reported seven unrelated NF1 microduplication patients. All seven microduplications span the entire NF1 gene and are reciprocal duplications of the known NF1 microdeletion regions; five patients had type I (1.4 Mb) or type II (1.2 Mb) duplications, one patient had a type III (1.0 Mb) duplication. The clinical features observed in more than one patient include variable developmental delay, facial dysmorphism, intellectual disability, and seizures. The finding of a normal carrier father of one of the patients in this study suggests incomplete penetrance.
18183042 Grisart et al (2008) reported seven patients in a family with 17q11.2 (NF1) microduplication which is reciprocal to the NF1 type I microdeletion. Five individuals presented similar phenotype including moderate mental deficiency, early onset of baldness, dental enamel hypoplasia, and mild facial dysmorphic features. Two duplication carriers displayed a normal phenotype, suggesting incomplete penetrance.
25205021 Kehrer-Sawatzki et al. (2014) reported two novel NF1 microduplication cases, one sporadic, another familial. Both index patients with NF1 duplications exhibited learning disabilities and atypical CALS. The mother and sister of one index patient also harbored the NF1 duplication and exhibited cognitive dysfunction but no CALS, demonstrating variable expressicivity.

Triplosensitivity phenotype comment:

Reciprocal duplications of the NF1 microdeletion region have been reported in more than 10 independent patients, although reduced penetrance and variable expressivity are well documented, patients with NF1 microduplication shared similar features including developmental delay/intellectual disability, mild facial dysmorphism. NF1 microduplication has not been reported in DGV and DDD control cases, and in a study comparing the relative frequency of 17q11.2 (NF1) microduplication in patients versus controls, Coe et al (PMID 25217958) observed enrichment in the patient population (p = 0.027), further supporting pathogenicity for duplication of this region.