ClinGen Dosage Sensitivity Curation Page

17q11.2 recurrent region (includes NF1)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

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.

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.