ClinGen Dosage Sensitivity Curation Page

16p11.2 recurrent region (distal, BP2-BP3) (includes SH2B1)

  • Curation Status: Complete
  • id: ISCA-37486
  • Date last evaluated: 2017-03-09
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 3
  • ClinGen Triplosensitivity Score: 1


Location Information

Select assembly: (NC_000016.9) ()
Evidence for haploinsufficiency phenotype
PubMed ID Description
20808231 Bachmann-Gagescu et al (2010) reported clinical phenotypes and provided a population-level prevalence comparison for 16p11.2 distal (SH2B1) deletion carriers identified by array CGH. Of 31 patients with deletions involving this region, 29 were unrelated and 9 patients (7 unrelated) had imbalances extending distal to the BP2-BP3-flanked 200 kb critical region. The atypical deletions included in this study did NOT extend into the critical region for the recurrent proximal BP4-BP5 region. A second genomic imbalance of clinical significance or uncertain clinical significance was observed in 6/31 (19.4%) of patients. Detailed clinical information was available for six patients, who all had developmental delays of varying severity. According to the authors, "four of the six patients had a BMI at or above the 95th percentile. All growth parameters including height, weight, and BMI were at or above the 95th percentile in three of these four patients, whereas weight and BMI were above the 95th percentile and height was above the 90th percentile in the fourth." The authors conclude that deletions of the 16p11.2 distal SH2B1-containing region are pathogenic and are associated with developmental delay, in addition to obesity. The deletion was shown to be significantly enriched (p=0.003) in the clinical population (31/23,084 patients) relative to controls (1/7700). Both inherited and de novo events were observed in the clinical cohort: 5/13 (38%) were de novo, 3 paternal and 5 maternal in origin.
19966786 Bochukova et al (2010) investigated the contribution of CNVs to obesity in 300 Caucasian patients with severe early-onset obesity, 143 also had developmental delay. The most common CNV enriched in patients with severe obesity was identified in 5 unrelated patients harboring deletions on 16p11.2 with a minimal overlapping segment of 220 kb. This 220-kb deletion (28.73?28.95 Mb NCBI36) was found in 2 of 7,366 controls; BMI data were unavailable. The minimal deleted region contains genes involved in neurological diseases (TUFM, ATP2A1), immunity (CD19, NFATC2IP, LAT) and genes of unknown function (ATXN2L, RABEP2, SPNS1), as well as SH2B1. They also sequenced SH2B1 in these patients but did not find any coding/splice site mutations. The 220-kb 16p11.2 deletion (28.73?28.95 Mb) was seen in three patients and co-segregated with severe early-onset obesity alone. They also used MLPA to test for SH2B1- containing (28.73?28.95 Mb) deletion in an independent set of 1,062 Caucasian patients with severe obesity alone from the same cohort and found two additional patients with this deletion. The prevalence of the SH2B1-containing deletion was lower in the replication cohort (2 out of 1,062) compared to the discovery set with severe obesity alone (3/157). Overall the prevalence of the SH2B1- containing deletion in patients with severe early-onset obesity alone (5/1,219; 0.41%) is significantly greater than in controls (2/7,366; 0.027%) (P < 0.001).
23258348 Rosenfeld et al (2013) conducted a Bayesian analysis, based on the CNV frequencies in control populations (n = 22,246) and in their database of postnatal array CGH samples and report 46/33,226 (0.14%) distal 16p11.2 (SH2B1) deletions compared to 1/22,246 (0.005%) controls (p= <<0.0001). The penetrance of this deletion was estimated to be 62.4% (95% CI: 26.8-94.4). Where inheritance information was available, the deletion was de novo in 7/21 (33.3%) of cases. Previously, Cooper et al (2011) performed a case-control analysis of 15,767 patients with DD/ID/MCA compared to 8,329 controls. The 16p11.2 distal (SH2B1) deletion was observed in 15 patients and 1 control individual (p=0.011). It is important to note that the Bachmann-Gagesu, Cooper and Rosenfeld datasets come from data from the Signature Genomics Laboratory. The Rosenfeld dataset represents an increase in the number of cases reported in the Cooper dataset. An additional, later study involving this dataset by Coe et al (2014) reported 16p11.2 distal deletion in 27/29,085 cases vs 1/19,584 controls (p =1.09E-05).

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 deletions and duplications involving recurrent breakpoint (BP) regions BP2 and BP3, located in the distal region of 16p11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Deletion of the distal 16p11.2 (SH2B1) region has been reported in association with a variable and incompletely penetrant phenotype that may include developmental delay, obesity, behavioral problems, schizophrenia, and craniofacial dysmorphism. Additional references: Barge-Schaapveld et al. 2011 PMID: 21465664 Guha et al 2013 PMID: 23325106 Loviglio et al. 2016 PMID: 27240531 PMID: 27869829

  • Triplosensitivity score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for gain of function phenotype
PubMed ID Description
27240531 Loviglio et al (2016) reviewed phenotypic information for 57 16p11.2 distal duplication carriers (representing 49 families) as part of their investigation of long-range chromatin interactions involving the 16p11.2 region. The study population (described in Supplementary Table S1) listed ascertainment modes with clinical indications (n=31) and ?general population? (n=18) and included 5 individuals whose data originated from the U.S. literature. Data on weight, height, body mass index (BMI) and head circumference (HC) were available for 39 unrelated carriers. Second-site structural variants were identified in 2/49 (4%) unrelated carrier probands. Duplication carriers were shown to have a statistically significant decrease in BMI and HC compared to a control population (p=0.005 and 1.1E-4, respectively; control population reported as previously described in Jacquemont et al., 2011, PMID: 21881559). In addition, the prevalence of autism spectrum disorders among duplication carriers was shown to be statistically different from the general population: 11/49; 22% versus 5,338/262,749; 1.5% (p=1.2E-10). The authors conclude that genomic rearrangements involving this region present large effect sizes on BMI and HC, as well as association with ASD.
23258348 Rosenfeld et al (2013) conducted a Bayesian analysis, based on the CNV frequencies in control populations (n = 22,246) and in their database of postnatal array CGH samples and report 35/33,226 (0.11%) distal 16p11.2 (SH2B1) duplications compared to 10/22,246 (0.04%) controls (p= <0.01). Penetrance for the duplication was estimated to be 11.2% (95% CI: 6.26-19.8). Where inheritance information was available, the duplication was de novo in 1/8 (12.5%) of cases. An additional, later study involving this dataset by Coe et al (2014) reported 16p11.2 distal duplication in 29/29,085 cases vs 8/19,584 controls (p=0.0137). Other prior studies of population-level prevalence involving the same (Signature Genomics Laboratory) dataset included Cooper et al (2011) (PMID: 21841781): 14/15,767 patients versus 2/8,329 controls (p=0.0484) and Bachmann-Gagescu et al. (2010) (PMID: 20808231): 17/23,084 patients versus 3/7,700 controls (p = 0.4).

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 deletions and duplications involving recurrent breakpoint (BP) regions BP2 and BP3, located in the distal region of 16p11.2. Note that genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. As clinical descriptions of affected duplication carriers are somewhat limited and consistent clinical findings have not been observed across all patients, the current triplosensitivity score is 1.