Chromosome 16p11.2 Duplication Syndrome

A number sign (#) is used with this entry because it represents a contiguous gene duplication syndrome (chr16:29.5-30.1 Mb, NCBI36).

Recurrent microdeletions and microduplications of approximately 555 kb at chromosome 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients (summary by Fernandez et al., 2010).

For a discussion of the clinical features and cytogenetics of the reciprocal 16p11.2 deletion, see 611913.

For an overview of other phenotypes associated with variation in pericentric region of chromosome 16, see 611913.

For a discussion of genetic heterogeneity of autism, see 209850.

Clinical Features

Shinawi et al. (2010) identified 27 individuals with a 16p11.2 deletion and 18 with a 16p11.2 duplication, accounting for 0.6% of 7,400 samples submitted for testing, most commonly for developmental delay and mental retardation. Ten patients with duplications were examined in detail. Among 5 families with duplication, 3 duplications were de novo and 2 were inherited, 1 from a slightly dysmorphic and microcephalic mother and the other from a cognitively impaired and microcephalic mother. Deletions or duplications within this region were not observed in 194 normal parental samples. Although neither group constituted a clearly clinically recognizable syndromes, there were some common phenotypic features. All probands showed speech/language delay and cognitive impairment. Those with duplications were more grossly dysmorphic compared to the deletion cases, but there was no recognizable pattern except microcephaly. Only 3 of 16 patients with the 16p11.2 deletion met criteria for autism, and only 2 with duplications had autistic features. However, patients from both groups had an increased incidence of other behavioral problems, most commonly attention-deficit hyperactivity disorder. All the deletions and duplications appeared to be recurrent and reciprocal, with a minimum size of 579 kb. Breakpoint analysis identified 2 major families of low copy repeat (LCR) regions, 147 kb and 72 kb repeats, respectively, that contributed to the genomic complexity in this region. Shinawi et al. (2010) emphasized the incomplete penetrance and variable expressivity of clinical findings in patients with these genomic abnormalities.

Fernandez et al. (2010) reported 5 autistic probands with copy number variation (CNV) at 16p11.2, including 3 with deletions and 2 with duplications, and 1 proband with duplication and developmental delay and autistic-like features. Proband 4 in the report, with a de novo duplication, had autism, epilepsy, congenital diaphragmatic hernia, hypertelorism, smooth philtrum, small ears, long slender fingers and toes, and decreased height and weight. Proband 5 was a 13-year-old girl who had an inherited duplication that was also present in her unaffected mother and sister. The last proband was a 26-month-old girl with autistic-like features and developmental delay who had inherited the duplication from her father, who had bipolar disorder. The child had frontal bossing with receding hairline, hypoplastic supraorbital ridges, sparse eyebrows and eyelashes, deep-set eyes, smooth philtrum, thin upper lip, and a flat facial profile. Fernandez et al. (2010) noted the extensive phenotypic variability in these patients, as some deletion-positive ASD probands had less severe phenotypes as deletion-negative ASD sibs. Compared with the microduplications, the microdeletions were more likely to be penetrant and to be associated with nonspecific major or minor dysmorphism. The results also indicated incomplete penetrance and supported the concept that sex difference provides a relative advantage in protecting females against the development of ASD even when a rare CNV is present.

Schaaf et al. (2011) reported 2 unrelated boys with heterozygous deletions of 16p11.2 and a third boy with a duplication of this region. The duplication patient had autism, academic deficits, mild mental retardation, attention deficit-hyperactivity disorder, anxiety, and behavioral problems. The patient with the duplication, who had a prominent neurobehavioral phenotype, inherited the duplication from his mother, who had an anxiety disorder; the maternal side of the family had a strong history of variable psychiatric disorders. The minimal size of the rearrangement in all 3 patients was 579 kb.

Mapping

Barnby et al. (2005) presented evidence for an autism susceptibility locus on chromosome 16p.

Cytogenetics

As a component of a genomewide association study of families from the Autism Genetic Resource Exchange (AGRE), Weiss et al. (2008) searched for recurrent copy number variations in the genotype data from 751 multiplex families with autism. Five children from 4 unrelated AGRE families carried de novo deletions. One pair of sibs who were not monozygotic twins carried the same de novo deletion. Reciprocal duplication of the same region was observed in 3 AGRE families; in 2 of these families the duplication was inherited, being transmitted from a parent to both affected offspring in one family, and from another parent to all 4 affected sons. Specific recurrent de novo events were further evaluated in data from Children's Hospital Boston and in a large population study in Iceland. These analyses identified a novel, recurrent 593-kb deletion and reciprocal duplication at chromosome 16p11.2 that carried substantial susceptibility to autism and appeared to account for approximately 1% of cases. No other regions with similar aggregations of large de novo mutations were identified.

Eichler and Zimmerman (2008) further discussed the hotspot of genomic instability at chromosome 16p11.2 associated with autism. Interspersed duplication blocks in this region promote unequal crossing-over during meiosis. Gametes are produced that either lack or carry a double dose of the critical interval. Dosage-sensitive differences of genes in the critical interval probably increase susceptibility to the disorder. Eichler and Zimmerman (2008) stated that more than 25 genes or transcripts are located in the critical interval.

Using high-resolution microarray analysis, Marshall et al. (2008) found 277 unbalanced copy number variations, including deletion, duplication, translocation, and inversion, in 189 (44%) of 427 families with autism spectrum disorder. These specific changes were not present in a total of about 1,600 controls, although control individuals also carried many CNV. Although most variants were inherited among the patients, 27 cases had de novo alterations, and 3 (11%) of these individuals had 2 or more changes. Marshall et al. (2008) detected 13 loci with recurrent or overlapping CNV in unrelated cases. Of note, CNV at chromosome 16p11.2 was identified in 4 (1%) of 427 families and none of 1,652 controls (p = 0.002). The 16p11.2 CNV region exhibited characteristics of a genomic disorder, including being flanked by a pair of segmental duplications with greater than 99% identity, which likely mediate the deletion/duplication events through nonallelic homologous recombination.

To investigate large copy number variants segregating at rare frequencies (0.1 to 1.0%) in the general population as candidate neurologic disease loci, Itsara et al. (2009) compared large CNVs found in their study of 2,500 individuals with published data from affected individuals in 9 genomewide studies of schizophrenia, autism, and mental retardation. They found evidence to support the association of CNV at chromosome 16p11.2 with autism and schizophrenia (CNV deletion P = 0.186; CNV duplication P = 0.100; locus P = 0.039). They identified 18 CNVs, either deletions or duplications, in this region; 14 of these were disease-associated.

Glessner et al. (2009) performed SNP analysis of candidate gene regions in 859 patients of European ancestry with autism spectrum disorder and 1,409 controls. They observed a similar frequency for deletions and duplications of the 16p11.2 locus in patients as compared to controls (about 0.3%). In addition, the CNVs at the 16p11.2 locus did not segregate to all cases in 3 affected families, and they were also transmitted to unaffected sibs, suggesting that the CNVs at the 16p11.2 locus may not be sufficient to be causal variants in autism spectrum disorder.

Levy et al. (2011) studied 887 families from the Simons Simplex Collection of relatively high functioning ASD families. They identified 75 de novo CNVs in 68 probands (approximately 8% of probands). Only a few were recurrent. Variation at the 16p11.2 locus was detected in more than 1% of patients (10 of 858), with deletions present in 6 and duplications in 4. In addition, the duplication at 7q11.2 of the Williams syndrome region (609757) was also seen as a recurrent CNV.

Sanders et al. (2011) examined 1,124 ASD simplex families from the Simons Simplex Collection. Each of the families was comprised of a single proband, unaffected parents, and in most kindreds an unaffected sib. Sanders et al. (2011) suggested that there are 130 to 234 ASD-related CNV regions in the human genome and presented compelling evidence, based on cumulative data, for association of rare de novo events at 7q11.23, 15q11.2-q13.1 (see 608636), 16p11.2, and neurexin-1 (600565). Sanders et al. (2011) found that probands carrying a 16p11.2 or 7q11.23 de novo CNV were indistinguishable from the larger ASD group with respect to IQ, ASD severity, or categorical autism diagnosis. However, they did find a relationship between body weight and 16p11.2 deletions and duplications. When copy number was treated as an ordinal variable, BMI diminished as 16p11.2 copy number increased (P = 0.02).

Sahoo et al. (2011) analyzed 38,779 individuals referred to the diagnostic laboratory for microarray testing for the presence of copy number variants encompassing 20 putative schizophrenia susceptibility loci. They also analyzed the indications for study for individuals with copy number variants overlapping those found in 6 individuals referred for schizophrenia. After excluding larger gains or losses that encompassed additional genes outside the candidate loci (e.g., whole-arm gains/losses), Sahoo et al. (2011) identified 1,113 individuals with copy number variants encompassing schizophrenia susceptibility loci and 37 individuals with copy number variants overlapping those present in the 6 individuals referred for schizophrenia. Of these, 1,035 had a copy number variant of 1 of 6 recurrent loci: 1q21.1 (612474, 612475), 15q11.2 (608636), 15q13.3 (612001), 16p11.2, 16p13.11 (610543, 613458), and 22q11.2 (192430, 608363). The indications for study for these 1,150 individuals were diverse and included developmental delay, intellectual disability, autism spectrum, and multiple congenital anomalies. The 16p.11.2 microduplication was seen in 59 individuals; 6 were de novo, 11 of maternal inheritance, 6 of paternal inheritance, and 36 of unknown inheritance; average age at diagnosis was 9.1 years, with an age range 0.7 to 25.3 years. This microduplication was seen in 59 of 23,250 cases referred to Sahoo et al. (2011) for a frequency of 0.25%. It was seen in 1 of 5,674 controls reported by Itsara et al. (2009), P = 0.0008. The frequency in the schizophrenia population compared to control population reported by McCarthy et al. (2009) was the same, but the frequency was 0.46 in the neurodevelopmental deficit population versus 0.02 in the control population reported by McCarthy et al. (2009). Sahoo et al. (2011) concluded that the results from their study, the largest genotype-first analysis of schizophrenia susceptibility loci to that time, suggested that the phenotypic effects of copy number variants associated with schizophrenia are pleiotropic and implied the existence of shared biologic pathways among multiple neurodevelopmental conditions.

Kaminsky et al. (2011) performed a large CNV case-control study comprising 15,749 International Standards for Cytogenomic Arrays (ISCA) cases with intellectual and developmental disabilities and 10,118 published controls, focusing their analysis on recurrent deletions and duplications involving 14 CNV regions. The 16p11.2 deletion was observed in 67 cases and the reciprocal duplication in 39 cases in the ISCA cohort, giving a frequency of 1 in 235 and 1 in 404, respectively.

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 (136570), the 16p11.2 duplication, 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.

Association of the 16p11.2 Duplication with Being Underweight

Jacquemont et al. (2011) showed that the 16p11.2 593-kb duplication is associated with being underweight. The authors identified 138 duplication carriers, including 132 novel cases and 108 unrelated carriers, from individuals clinically referred for developmental or intellectual disabilities or psychiatric disorders, or recruited from population-based cohorts. The carriers showed significantly reduced postnatal weight and BMI. Half of the boys younger than 5 years were underweight with a probable diagnosis of failure to thrive, whereas adult duplication carriers had an 8.3-fold increased risk of being clinically underweight. Jacquemont et al. (2011) observed a trend towards increased severity in males, as well as a depletion of male carriers among non-medically ascertained cases. These features were associated with an unusually high frequency of selective and restrictive eating behaviors and a significant reduction in head circumference. Each of the observed phenotypes is the converse of one reported in carriers of deletions at this locus. The phenotypes correlated with changes in transcript levels for genes mapping within the duplication but not in flanking regions. The authors concluded that the reciprocal impact of these 16p11.2 copy number variants indicated that severe obesity and being underweight could have mirroring etiologies, possibly through contrasting effects on energy balance. The 16p11.2 duplication was identified with a frequency of 0.23% (95% confidence interval (CI), 0.18-0.29) within a cohort of patients with neurodevelopmental disorders. The frequency was 0.37% (95% CI, 0.01-0.73) among patients with a family history of adult psychiatric symptoms. It was not identified in any cohorts of obese patients and was identified as having a population-based frequency of 0.05% (95% CI, 0.03-0.07) using Finnish, Swiss, Estonian, Icelandic, and German cohorts, and a pediatric family study.

Animal Model

Golzio et al. (2012) dissected a region of the 16p11.2 chromosome, which encompasses 29 genes, that confers susceptibility to neurocognitive defects when deleted or duplicated. Overexpression of each human transcript in zebrafish embryos identified KCTD13 (608947) as the sole message capable of inducing the microcephaly phenotype associated with the 16p11.2 duplication, whereas suppression of the same locus yielded the macrocephalic phenotype associated with the deletion, capturing the mirror phenotypes of humans. Analyses of zebrafish and mouse embryos suggested that microcephaly is caused by decreased proliferation of neuronal progenitors with concomitant increase in apoptosis in the developing brain, whereas macrocephaly arises by increased proliferation and no changes in apoptosis. A role for KCTD13 dosage changes was consistent with autism in both a family with a reduced 16p11.2 deletion (Crepel et al., 2011) and a subject reported by Golzio et al. (2012) with a complex 16p11.2 rearrangement involving de novo structural alteration of KCTD13. Golzio et al. (2012) concluded that their data suggested that KCTD13 is a major driver for the neurodevelopmental phenotypes associated with the 16p11.2 CNV, reinforced the idea that one or a small number of transcripts within a CNV can underpin clinical phenotypes, and offered an efficient route to identifying dosage-sensitive loci.