16p12.2 recurrent region (proximal) (includes EEF2K, CDR2)

Girirajan et al. (2010) performed a meta-analysis comparing the frequency of 16p12.2 (formerly mapped to 16p12.1) region microdeletions in two separate cohorts (discovery and replication sets) of individuals referred for clinical genomic microarray testing (with developmental and neurocognitive indications) compared to controls. The 16p12.2 microdeletion was identified in 20/11,873 cases vs. 2/8,540 controls in the discovery set (p=0.0009; OR=7.2) and in 22/9,254 vs. 6/6,299 controls in the replication set (p=0.028, OR=2.5). Combined, the frequency of 16p12.2 microdeletion in the patient population, “was highly significant” (p=1.18x10^-4, OR=3.7). Clinical indications in common across patients included developmental delay, speech delay, craniofacial/skeletal features, and a variety of additional, variably penetrant phenotypic features. Inheritance studies showed most 16p12.2 deletions were inherited (22/23; 95.7%), with carrier parents more likely to manifest neurological or neuropsychiatric phenotypes (learning disability, depression, bipolar disorders, seizures) compared to non-carrier parents (p=0.037, OR=6). Only three carrier parents were unaffected. In general, parental phenotypes were less severe than the index probands. A subset of 16p12.2 deletion carriers (10/42, 23.8%) had a second large (>500 kb) CNV; of patients with a separate syndromic CNV, distinct features and/or greater clinical severity was generally observed. Compared to matched controls, second-hit CNVs were more common in the affected probands (21/471 controls, p=5.7x10^-5, OR=6.6). The authors also showed the 16p12.2 microdeletion was NOT enriched in a separate, smaller cohort of patients with schizophrenia (3/3061 cases vs 8/14,839 controls; p=0.29, OR=1.8). The authors propose, “…the 16p12.2 microdeletion might be a risk factor for neurodevelopmental disease that also acts with other large CNVs to modify neuropsychiatric phenotypes, thereby supporting a ‘two-hit” model for the generation of severe cognitive deficits involving this region.”

Rees et al. (2014) performed a large case-control study to discover novel CNVs associated with schizophrenia. Deletion of 16p12.2 was observed in 13/6882 cases vs. 6/11,255 controls in the discovery sample (p=0.0084), and in 20/14,568 cases vs. 9/15,274 controls in the replication sample (p=0.023). Combined, the deletion was significantly enriched in the clinical cohort (p=0.0016; OR=2.72, range: 1.48-5.02). Only one case had a second-hit CNV from the discovery set. The authors report deletions at 16p12.1, “as the most likely new risk locus” for schizophrenia and note, “The combination of a modest OR for developing schizophrenia and a low frequency could explain why it has not been identified until now (our discovery sample has <80% power to detect its association at alpha 0.05)”.

D'Alessandro et al. (2014) performed a case-control study for left-sided heart lesions (LHL) to assess whether there was an increased frequency of 16p12.2 microdeletion in this cohort. Control cases included individuals with conotruncal heart defects, but not LHL. One individual in each group was identified with deletion, and none had dysmorphic features, extracardiac malformations, or developmental delay. The authors note this deletion is not found with increased frequency in LHL subjects compared to controls.