ClinGen Dosage Sensitivity Curation Page

17q11.2 recurrent region (includes NF1)

  • Curation Status: Complete
  • id: ISCA-37431
  • Date last evaluated: 2020-10-12
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 2


Location Information

Select assembly: (NC_000017.10) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
20513137 Pasmant et al. (2010), described 70 patients with NF1 deletions including 54 recurrent type-1, 6 recurrent type-2, and 3 recurrent type-3. The clinical findings associated with this deletion include features of Neurofibromatosis 1 (including neurofibromas, caf? au lait spots, freckling, Lisch nodules, optic gliomas), scoliosis, facial dysmorphisms, learning disabilities, and additional clinical findings. Of note, patients with type-1 17q11.2 deletions were more likely to present with facial dysmorphisms and learning disabilities than patients with NF1 due to sequence level variants. Approximately 17% of patients with recurrent deletions in this study were found to have inherited the deletion (7/47 type-1, 2/6 type-2, 0/3 type-3).
20543202 Mautber et al. (2010), described 29 patients with 17q11.2 recurrent type-1 deletion. The clinical findings associated with this deletion include features of Neurofibromatosis 1 (including neurofibromas, caf? au lait spots, freckling, Lisch nodules, optic gliomas), facial dysmorphisms, intellectual disability, learning disabilities, attention deficit hyperactivity disorder, cardiac anomalies, scoliosis, and additional clinical findings. Approximately 7% of the patients in this study were found to have inherited the deletion.
22151963 Vogt et al. (2011), described 2 patients with 17q11.2 recurrent type-2 deletion. The clinical findings observed in these two patients included neurofibromas, axillary/inguinal freckling, lisch nodules, macrocephaly, facial dysmorphisms, learning disability, attention deficits, congenital heart defects, and additional clinical findings. Parental testing was not noted reported.

Haploinsufficiency phenotype comments:

Deletion of the 17q11.2 recurrent region*, encompassing the gene Neurofibromin 1 and other neighboring genes, is associated with neurofibromatosis type I (NF1). This deletion accounts for approximately 5% cases of NF1. Although patients with the 17q11.2 deletion show a variable clinical phenotype, similar to patients with gene-level pathogenic variants, genotype-phenotype correlation studies have shown that 17q11.2 deletion carriers may have larger numbers and earlier appearance of cutaneous neurofibromas, higher incidence and more severe cognitive abnormalities, facial dysmorphisms, and overgrowth (PMID: 20301288). Genotype-phenotype correlations across different 17q11.2 deletion types have not yet been demonstrated. Approximately 17% of patients with the recurrent 17q11.2 deletion have inherited it from a parent (PMID: 20513137). Deletions of this region are enriched within the clinical population (summarized below). Given the presence of a known haploinsufficient gene within this region (NF1), the enrichment of deletions within the clinical population, and the association of deletions with a specific clinical phenotype, the haploinsufficiency score for this region is a 3. *The proximal 17q11.2 region contains a cluster of low-copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. The type 1 deletion is 1.4 Mb, and is mediated by LCRs NF1 repeat (-REP) A and NF1 -REP C. The type 2 deletion is 1.2 Mb, with breakpoints within SUZ12 and SUZ12P. The type 3 deletion is 1.0 Mb, and is mediated by NF1-REP B and NF1-REP C. This review includes all three regions, but has breakpoints that align with the unique sequence associated with type 2 deletions. Additional relevant literature is summarized below: Case-control studies: PMID 25217958: Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, deletions of the recurrent 17q11.2 recurrent region were observed in 7/29,085 cases versus 0/19,584 controls (p=0.027; LR: Inf, CI: 1.23 to Inf). PMID 20301288: GeneReviews article: Neurofibromatosis 1

  • Triplosensitivity score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for triplosensitivity phenotype
PubMed ID Description
22241097 Moles et al. (2012) reported seven unrelated patients with 17q11.2 (NF1) duplications. 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 included developmental delay, intellectual disability, facial dysmorphisms, and seizures. Parental testing was performed on three of the reported duplications. Two out of three duplications were found to be inherited, with one being inherited from a clinically normal father and the other being inherited from an affected mother who had dysmorphic features similar to her son and language delay.
18183042 Grisart et al. (2008) reported seven patients in a family with a 17q11.2 (NF1) type I duplication. Five individuals in this family presented with a similar phenotype, including moderate mental deficiency, developmental delay, early onset of baldness, dental enamel hypoplasia, and mild dysmorphic facial features. Two duplication carriers from this family displayed a normal phenotype, suggesting incomplete penetrance.
25205021 Kehrer-Sawatzki et al. (2014) reported two 17q11.2 (NF1) duplication cases. These patients were reported to have learning disabilities, intellectual disability, developmental delay, atypical cafe au lait spots (CALS), and mild dysmorphic facial features. NF1 gene mutation testing was negative for both patients. The duplication was de novo in one patient (R653070). The other patient (R609021) had inherited it from his mother and also had a sister who was a carrier of the duplication. The mother and sister exhibited cognitive dysfunction but no CALS, demonstrating variable expressivity.

Triplosensitivity phenotype comment:

Duplication of the 17q11.2 recurrent region* has been reported in over 10 independent families (approximately 17 patients). Clinical findings that are consistently observed include developmental delay/intellectual disability and mild facial dysmorphisms. Additional findings have been reported in a few patients including seizures, dental enamel hypoplasia, early onset baldness, short stature, and failure to thrive, although these findings are not consistently observed across all patients. Parental testing has demonstrated that four out of six of the reported duplications were inherited, and that most are inherited from an affected parent; however, two families have also been found to have unaffected carriers. Case-control studies have shown enrichment of this duplication in the clinical population (summarized below). Due to the limited number of 17q11.2 duplication cases reported in the literature, the phenotypic non-specificity/variability observed in affected carriers, and the presence of unaffected carriers in multiple families, the triplosensitivity score for this region is a 2. *The proximal 17q11.2 region contains a cluster of low-copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. The type 1 duplication is 1.4 Mb, and is mediated by LCRs NF1 repeat (-REP) A and NF1 -REP C. The type 2 duplication is 1.2 Mb, with breakpoints within SUZ12 and SUZ12P. The type 3 duplication is 1.0 Mb, and is mediated by NF1-REP B and NF1-REP C. This review includes all three regions, but has breakpoints that align with the unique sequence associated with type 2 duplications. Additional relevant literature is summarized below: Case-control studies: PMID 25217958: Coe et al. (2014): In a large-scale case-control comparison study of the relative prevalence of copy number variants in children with ID/DD, MCA, and other developmental phenotypes compared to controls, duplications of the recurrent 17q11.2 recurrent region were observed in 7/29,085 cases versus 0/19,584 controls (p=0.027; LR: Inf, CI: 1.23 to Inf). Additional Cases: PMID 27629806: Koczkowska et al. (2017): report of a single patient with a duplication of the recurrent 17q11.2 NF1 region. The patient was reported to have dysmorphic craniofacial findings. Learning difficulties/developmental delay and seizures were reported to be absent. Parental testing was not reported.