Chromosome 16p12.1 Deletion Syndrome, 520-Kb

A number sign (#) is used with this entry because it represents a contiguous gene deletion syndrome (chr16:21.85-22.37 Mb).

Description

There are several phenotypes associated with variation in pericentric region of chromosome 16: see the 16p12.2-p11.2 deletion syndrome (613604); see 611913 for a deletion or duplication at 16p11.2 associated with autism (AUTS14); and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay.

Clinical Features

Girirajan et al. (2010) identified 42 probands with developmental delay, craniofacial dysmorphology, and congenital heart defects carrying a recurrent 520-kb heterozygous microdeletion of chromosome 16p12.1. Evaluation of available medical records showed that most probands had developmental delay and learning disability. All 15 individuals who were older than 12 months had speech delay. Craniofacial and skeletal abnormalities were observed in 22 of 23 cases, growth retardation was documented in 9 of 22 cases, and microcephaly was present in 7 of 20. Seven of 21 had congenital cardiac disease, including 4 with a hypoplastic left heart syndrome. Seizure disorders were observed in 8 of 22 cases, and hypotonia was present in 10 of 21 cases. Psychiatric and behavioral abnormalities were also documented in 9 of 16 affected children.

Molecular Genetics

By genomewide metaanalysis, Girirajan et al. (2010) identified a recurrent 520-kb heterozygous microdeletion of chromosome 16p12.1 that was associated with susceptibility to childhood developmental delay or intellectual disability, including schizophrenia (181500). The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (p = 0.0009; OR, 7.2), and the finding was replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (p = 0.028; OR, 2.5). The results for the combined set yielded a highly significant association (p = 1.18 x 10(-4); OR, 3.7). Using high-density and targeted array-based comparative genomic hybridization (CGH) of a recurrent microdeletion of 16p12.1, Girirajan et al. (2010) mapped the breakpoints in 37 individuals to 2 large blocks of segmental duplications with a 68-kb duplicon in direct orientation in relation to its paralog in the distal breakpoint region. This duplicon predisposed to nonallelic homologous recombination (NAHR) events resulting in microdeletions. The boundaries of the breakpoints could not be refined below 100 kb. Most deletions were inherited (22 of 23 cases), and carrier parents were more likely to manifest neuropsychiatric phenotypes compared to noncarrier parents (p = 0.037; OR, 6.0). In addition, affected probands were more likely to carry an additional large copy-number variant (10 of 42, 24%) when compared to controls (21 of 471, 4.4%; p = 5.7 x 10(-5)), and the clinical features of individuals with 2 genomic anomalies were distinct from and/or more severe than those with 1 microdeletion. Girirajan et al. (2010) stated that their data support a 2-hit model in which the 16p12.1 microdeletion predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Although there was variable phenotypic expressivity, the model was generally applicable to neuropsychiatric disease.

Girirajan et al. (2012) analyzed the genomes of 2,312 children known to carry a copy number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. Among the affected children, 10.1% carried a second large copy number variant in addition to the primary genetic lesion. Girirajan et al. (2012) identified 7 genomic disorders, each defined by a specific copy number variant, in which the affected children were more likely to carry multiple copy number variants than were controls. These included the 16p12.1 deletion, the 16p11.2 duplication (614671), and the 15q11.2 deletion (608636). They found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy number variants and whether the variants are inherited or de novo. Children who carried 2 large copy number variants of unknown clinical significance were 8 times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11 x 10(-38)). Among affected children, inherited copy number variants tended to co-occur with a second-site large copy number variant (Spearman correlation coefficient, 0.66; P less than 0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P less than 0.001), and mothers were more likely than fathers to transmit second-site copy number variants to their offspring (P = 0.02). Girirajan et al. (2012) concluded that multiple, large copy number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy number variants are preferentially transmitted from maternal carriers.

Evolution

Antonacci et al. (2010) performed a detailed analysis of 1 region on chromosome 16p12.1 associated with neurocognitive disease and identified one of the largest structural inconsistencies in the human reference assembly. Various genomic analyses show that all examined humans are homozygously inverted relative to the reference genome for a 1.1-Mb region on 16p12.1. Antonacci et al. (2010) determined that this assembly discrepancy stems from 2 common structural configurations with worldwide frequencies of 17.6% (S1) and 82.4% (S2). This polymorphism arose from the rapid integration of segmental duplications, precipitating 2 local inversions within the human lineage over the last 10 million years. The 2 human haplotypes differ by 333 kb of additional duplicated sequence present in S2 but not in S1. Notably, Antonacci et al. (2010) showed that the S2 configuration harbors directly oriented duplications, specifically predisposing this chromosome to disease-associated rearrangement. Among Asians the S1 frequency is 0.28 with an S2 frequency of 0.72; among Yorubans the S1 frequency is 0.03 with an S2 frequency of 0.98; among Europeans the S1 frequency is 0.17 with an S2 frequency of 0.83; and in microdeletion samples the S1 frequency is 0.01 with an S2 frequency of 0.99.