ClinGen Dosage Sensitivity Curation Page

16p11.2 recurrent region (proximal, BP4-BP5) (includes TBX6)

Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
20301775 GeneReviews article (https://www.ncbi.nlm.nih.gov/books/NBK11167/)
18184952 Weiss et al. (2008) reported de novo deletions of this region at 16p11.2 in 10 patients with autism, developmental delay, and/or intellectual disability from three different large patient samples. Two deletions were inherited from parents with ADHD or intellectual disability and the inheritance of one is unknown. The deletion was not found in patients who had microarray testing for other indications such as dysmorphic features or congenital abnormalities. Overall, this deletion was found in 1-1.5% of patients, depending on the sample, which is significantly more frequent than in the general population. The authors also note that the deletion was found in 0.1% of patients with a psychiatric or language disorder, compared to 0.01% in the general population.
21841781 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, 16p11.2 (TBX6) proximal region deletions were observed in 101/29,085 cases versus 6/19,584 controls (p=2.07E-16), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 25424174 and Rosenfeld et al. (2013) PMID 23258348.

Evidence for Triplosenstive Phenotype

Evidence for triplosensitivity phenotype
PubMed ID Description
18184952 Weiss et al. (2008) reported duplications of this region at 16p11.2 in three families with autism from one clinical cohort and reduced penetrance was noted. It was not found in any controls. In another clinical cohort, the duplication was found in four patients with autism or intellectual disability/developmental delay, but not in any patients who had testing for other diagnoses. In a third cohort, the duplication was not found in any patients with autism, but was observed in two patients with bipolar disorder and five unscreened controls.
21731881 Rosenfeld et al. (2010) reported duplications of this region at 16p11.2 in 32 patients who had clinical microarray testing for various reasons. Five were de novo, 14 were inherited, and inheritance was unknown for 13. Three patients had an autism spectrum disorder. Four patients had another clinically relevant CNV observed. Detailed clinical information was available for 10 patients and frequent characteristics included delayed development, speech delay, behavioral problems, and variable dysmorphic features. However, some of these patients also had other unrelated diagnoses (Beckwith-Wiedemann syndrome, PKU, and methylmalonic aciduria) or a history of abuse.
21841781 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, 16p11.2 (TBX6) proximal region duplications were observed in 62/29,085 cases versus 9/19,584 controls (p=3.50E-07), demonstrating enrichment of this duplication in the clinical population. See also Cooper et al. (2011) PMID 25424174 and Rosenfeld et al. (2013) PMID 23258348.

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.