ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37400
  • Date last evaluated: 2017-02-09
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 3


Location Information

Select assembly: (NC_000016.9) ()
Evidence for haploinsufficiency 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.

Haploinsufficiency phenotype comments:

The 16p11.2 region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions and duplications involving recurrent breakpoint (BP) regions BP4 and BP5, located in the proximal region of 16p11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Clinical features associated with 16p11.2 (TBX6) proximal region deletion may include: developmental delay; cognitive impairment; language delay; autism spectrum disorder; delayed language development (with more receptive than expressive language abilities); minor dysmorphic facial features that do not represent a consistent, recognizable pattern; neurologic issues including seizures or electroencephalogram abnormalities; obesity; psychiatric diseases; and cardiac malformations. Incomplete penetrance has been observed. For additional references regarding the phenotype of 16p11.2 haploinsufficiency: Hanson E, et al., 2016: PMID 25064419 Steinman KJ, et al., 2016: PMID 27410714 Zufferey F, et al., 2012: PMID 23054248 Bijlsma et al. (2009) PMID 19306953 reported deletions of this region at 16p11.2 in 14 of 4284 patients tested due to intellectual disability or congenital anomalies (0.3%). Six were de novo, six were inherited from parents with a mild or normal phenotype, and inheritance was unknown for two. Common clinical features included dysmorphic facial features, developmental delay of variable severity, and obesity. Only one patient had a formal autism diagnosis.

Evidence for gain of function 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.

Triplosensitivity phenotype comment:

The 16p11.2 region contains a cluster of low copy repeats that mediate recurrent copy number changes through non-allelic homologous recombination. This review refers to deletions and duplications involving recurrent breakpoint (BP) regions BP4 and BP5, located in the proximal region of 16p11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Clinical features associated with 16p11.2 (TBX6) proximal region duplication may include: developmental delays (including speech, language and motor delays), intellectual disability, autism spectrum disorder, behavioral problems (including ADHD), psychiatric disorders, seizures, microcephaly, decreased body mass index, congenital anomalies, and additional variable clinical findings. Incomplete penetrance has been observed. For additional references regarding the phenotype of 16p11.2 triplosensitivity: D'Angelo D, et al., 2016: PMID 26629640 Steinman KJ, et al., 2016: PMID 27410714