ClinGen Dosage Sensitivity Curation Page

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

  • Curation Status: Complete
  • id: ISCA-37409
  • Date last evaluated: 2018-03-23
  • Issue Type: ClinGen Region Curation
  • ClinGen Haploinsufficiency Score: 2
  • ClinGen Triplosensitivity Score: 0


Location Information

Select assembly: (NC_000016.9) ()
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
20154674 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.?
24163246 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)?.
23682798 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.

Haploinsufficiency phenotype comments:

Deletion of 16p12.2 has been observed in association with an incompletely penetrant and variable spectrum of clinical phenotypes including developmental delay, mild to moderate intellectual disability, speech delays, psychiatric and behavioral abnormalities, mild dysmorphic features without a consistent pattern, congenital cardiac defects, sleep disturbance, and epilepsy. This deletion has been proposed to be a susceptibility locus for neurodevelopmental and neuropsychiatric phenotypes. The 16p12.2 deletion has also been observed in normal-random-controls (not phenotypically characterized) and in unaffected relatives. This deletion is most often inherited. Although 16p12.2 deletion has been shown to be enriched in the clinical population across certain studies, at least one study of patients with heart defects did not show clinical enrichment (D'Alessandro et al., 2014). The 16p12.2 region shows structural polymorphism, with two flanking LCR configurations (the more common, direct orientation predisposes this region to producing CNVs) and varies across different human populations; thus there is the potential for biased association due to population sampling error. In at least one study (Rees et al., 2014), restriction of the comparative frequency analysis to individuals of European decent showed greater enrichment in the clinical population. Due to the broad phenotypic variability, low overall penetrance, presence of structural polymorphism, and the presence of conflicting data associated with 16p12.2 deletion, the current haploinsufficiency score is 2. Note that previously this region was mapped to chromosome band 16p12.1 and is referred to by this designation in some earlier literature. Genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. Additional relevant literature is summarized below. PMID 25719193: GeneReviews: https://www.ncbi.nlm.nih.gov/books/NBK274565/ PMID 25217958: 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, 16p12.2 region deletions were observed in 50/29,085 cases versus 11/19,584 controls (p=1.77E-04; LR=3.06, range=1.72 to 5.61), demonstrating enrichment of this deletion in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348. PMID: 24352232 Stefansson et al. (2014) recruited adults aged 18-65 years from a large genotyped control population from Iceland to evaluate whether CNVs previously reported in affected populations are associated with cognitive and psychiatric phenotypes in control individuals who carry these CNVS, compared to control individuals who do not. Seven 16p12.2 deletion carriers were included in this study. Six CNVs were found to be associated (with large effects) with decreased verbal and/or performance IQ in carrier controls, including 16p12.2 deletions (V IQ Effect=2.05; p=8.30E-6). 16p12.2 deletions were also associated with increased fecundity, the significance of which was not discussed. PMID: 24813870 Rai and Sharif (2015) report on a single individual with a paternally inherited 16p12.2 deletion who presented with motor delay and cognitive impairment. Brain MRI revealed ventriculomegaly secondary to narrowing of the spinal canal at the cervicomedullary junction. No clinical information about the father was provided.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

Due to lack of reported clinical association of 16p12.2 duplications, as well as lack of supportive case-control data, there is currently insufficient evidence to support triplosensitivity of this region; therefore the triplosensitivity score is 0. Note that previously this region was mapped to chromosome band 16p12.1 and is referred to by this designation in some earlier literature. Genes used as landmarks are not necessarily causative of the complete phenotype(s) associated with the region. PMID 25217958: 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, 16p12.2 region duplications were observed in 11/29,085 cases versus 4/19,584 controls (p=0.2120; LR=1.85, range=0.62-6.04); thus 16p12.2 duplication was not observed to be enriched in the clinical population. See also Cooper et al. (2011) PMID 21841781 and Rosenfeld et al. (2013) PMID 23258348.