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

Loviglio et al. (2017) compared BMI, head circumference, and prevalence of autism in a cohort of 110 clinically-ascertained individuals with intellectual disability/developmental delay and obesity from 88 families with the 16p11.2 distal deletion with that of general population controls, as part of their investigation of long-range chromatin interactions. Autism was observed in 23/88 (26%) of deletion carriers. The prevalence of autism was significantly higher in this cohort as compared to the general population (1.5%, 5,338/363,749) (p=2.5E-22, OR = 23.7, Fisher’s exact test). A trend towards obesity (significant, BMI mean Z-score, p=3.1E−14, t-test) and macrocephaly (increased head circumference, HC) was also observed compared to the general population. Second-site deleterious structural variants were identified in 6/88 (7%) of unrelated probands which was notably lower than a previous study (Bachmann-Gagescu et al., 2010; PMID 20808231). The authors also performed analysis of chromatin interactions between the distal and proximal 16p11.2 regions, which have overlapping phenotypes (autism, BMI, HC), using 4C-sequencing, FISH, and Hi-C methods and found evidence of physical and functional interaction between these regions.

Bachmann-Gagescu et al. (2010) reported clinical findings associated with 16p11.2 distal deletions in a cohort of patients referred for clinical array CGH testing. A total of 31 patients (29 unrelated) with deletions involving the distal BP2-BP3 region (22 typical BP2-BP3, 9 atypical extending distally into BP1-BP2) were identified. A second genomic imbalance was identified in 6/31 (19%) of patients, 2 of which were pathogenic. Detailed clinical information was available for 6 patients, all of whom had developmental delay/intellectual disability, and none of whom had an additional CNV. Obesity (BMI at or above the 95th percentile) was observed in 4/6 individuals. Additional variable findings in at least 2 patients included speech delay, neuropsychiatric/behavioral problems, and autism. Variable congenital anomalies and dysmorphic features were also observed but were inconsistent across patients. The deletion was de novo in 5/31 cases, maternally inherited in 5/31 cases, paternally inherited in 3/31 cases, and inheritance was unknown in the remaining 18/31 cases. Clinical information for deletion carrier parents was not available. Case-control comparison showed the 16p11.2 distal deletion was enriched in patients (31/23,084; 0.13%) compared to a combined control dataset (1/7700; 0.013%) (p=0.003).

Bochukova et al. (2010) used SNP-microarray to identify CNVs in a cohort of 300 patients with severe early-onset obesity, of which a subset (n=143) also had developmental delay (DD). The 16p11.2 distal deletion was identified in 3/157 patients with severe early-onset obesity alone (not seen with DD). MLPA-targeted testing within the 16p11.2 region on a second set of 1062 patients with severe obesity alone identified 2 additional individuals (5 total probands with severe obesity). The deletion was inherited from a parent with obesity in 4/4 individuals where inheritance information was available. Case-control comparison showed the 16p11.2 distal deletion was enriched in patients with severe early-onset obesity alone (5/1,219; 0.41%) compared to a selected group of controls (2/7,366; 0.027%) (p<0.001), although BMI data were not available for the 16p11.2 distal deletion carrier control individuals. Sequencing of the candidate gene SH2B1 within the deleted interval of patient samples did not identify a pathogenic variant on the other allele, suggesting a haploinsufficient mechanism of pathogenicity.

Kendall et al. (2019) analyzed the effect of the 16p11.2 distal deletion on cognitive performance and general measures of functioning of 58 deletion carrier adults recruited from the UK Biobank cohort (a large, genotyped group from the general population) compared to non-carrier controls from the same population. Significant differences were observed for 7 of 11 total measurements, including 3 of 7 cognitive measures and 4 of 4 measures of general functioning, the latter of which are not included for CNV evidence scoring. Penetrance for any clinical phenotype associated with this deletion was estimated to be 23% using a previously reported clinical cohort compared to the UK Biobank control database. See also Owen et al. (2018) PMID 30509170 and Macé et al. (2017) PMID 28963451, which use overlapping datasets and showed significant associations of the 16p11.2 distal deletion with high BMI, weight, and other anthropometric traits.

Barge-Schaapveld et al. (2011) reported clinical findings of 5 patients from 2 unrelated families with 16p11.2 distal deletions. Clinical features in common in least 3 individuals included developmental delay, craniofacial dysmorphism, behavioral problems, and obesity. In one family, the deletion was inherited from the patient’s father, and detected in the patient’s a sister, both of whom had a history of obesity. In the other family, the father died at a young age and was not tested for the deletion; however, he presented with a phenotype similar to that of his affected sons (learning difficulties, behavioral problems, and dysmorphic facial features), and was presumed to carry the deletion.

Guha et al. (2013) studied the prevalence of recurrent CNVs in multiple discovery and replication schizophrenia (SZ) case and control cohorts. The 16p11.2 distal deletion was the only CNV shown to be enriched, with a prevalence of 13/13,850 cases (6 typical BP2-BP3 and 7 BP1-BP3 deletions) versus 3/19,954 controls (Fisher's exact test p = 0.0014; OR = 6.25, 95% CI: 1.78 – 21.93). Phenotypic data was available for a subset of carrier individuals and did not include intellectual disability or a specific clinical profile. Two cases were obese/overweight, and two cases and one control had type 2 diabetes. Where studied, the deletion was maternally inherited in 2 cases from mothers with no history of psychotic disorders, one was noted to have a mood disorder.