Other entities represented in this entry:
ORPHA: 261197; DO: 0070515;
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38): 16:28,500,001-35,300,000
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | {Autism susceptibility 14A} | 611913 | 2 | |
| Chromosome 16p11.2 deletion syndrome, 593kb | 611913 | 4 |
A number sign (#) is used with this entry because it represents a contiguous gene deletion 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). The 16p11.2 deletion frequently cosegregates with severe early-onset obesity (Bochukova et al., 2010; Walters et al., 2010).
There are several phenotypes associated with variation in pericentric region of chromosome 16: see the 16p12.2-p11.2 deletion syndrome (613604); see 136570 for discussion of a recurrent 520-kb deletion at 16p12.1 associated with developmental delay and craniofacial dysmorphism; and see 613444 for a 220-kb deletion at 16p11.2 associated with isolated severe early-onset obesity and obesity with developmental delay.
For a discussion of the clinical features and cytogenetics of the reciprocal 16p11.2 duplication, see 614671.
Battaglia et al. (2009) emphasized that the region at 16p11.2 that confers susceptibility to autism is located more centromeric to and is distinct from 16p12.2-p11.2 region involved in the multiple congenital anomalies and intellectual disabilities phenotype (613604).
For a discussion of genetic heterogeneity of autism, see 209850.
Hernando et al. (2002) reported the first case of multiple congenital anomalies associated with a de novo interstitial deletion of band 16p11.2 confirmed by array comparative genomic hybridization (CGH). Ultrasound examination at age 20 weeks' gestation showed cardiac defects and unilateral multiple renal cysts. At birth, the male infant showed severe intrauterine growth retardation and dysmorphic features, including flat facies, microretrognathia, blepharophimosis, short nose with hypoplastic nasal alae and absent nasal bridge, low-set and malformed ears, coloboma, and unilateral chorioretinitis. Other features included tetralogy of Fallot with pulmonary atresia, cubital deviation of the hands, talipes varus, articular limitation, and hemivertebra at level L1. He also had unilateral renal agenesis and cryptorchidism. The deletion occurred on the maternally derived chromosome. He died of cardiac failure at age 5 months.
Shimojima et al. (2009) reported a 3-year-old boy with intrauterine growth retardation who had developmental delay, multiple hemivertebrae, missing ribs, inguinal hernia, and hydrocele testis. He could stand without support, but was unable to communicate verbally and showed hyperactivity, but did not fulfill the criteria for autism. He had mild dysmorphic features with microcephaly, bilateral ptosis, and a long nose. Brain MRI showed mild dilatation of the lateral ventricles. Array CGH identified an interstitial 593-kb deletion on chromosome 16p11.2 between homologous segmental duplications. The deletion was identical to the common deletion previously identified in patients with autism spectrum disorder (Weiss et al., 2008; AUTS14; see CYTOGENETICS). The mother also carried the deletion and was suspected to be borderline mentally retarded, but did not have autism and was not formally tested. Shimojima et al. (2009) noted that the patient reported by Hernando et al. (2002) also had hemivertebrae, and postulated involvement of the TBX6 gene (602427).
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. Sixteen patients with deletions were examined in detail. The deletion was confirmed to be de novo in 8 of 10 families, and was inherited from an affected father or an asymptomatic healthy parent in 1 family each. 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 deletions had macrocephaly, broad forehead, micrognathia, hypertelorism, and a flat midface. Deletion carriers had motor delay (50%), seizures (40%), and congenital anomalies (30%). 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. Two of the 3 probands with deletions had notable dysmorphic features. The first proband was a 13-year-old boy with low nuchal hairline, short neck, flat face, low-set ears, narrow palpebral fissures, short nose with flat broad nasal root, smooth philtrum, widely spaced upper incisors, and pointed chin. He also had small hands with distally tapered fingers, short toes, micropenis, and obesity. He carried a de novo deletion. His sister, who did not carry the deletion, had Asperger syndrome and was not dysmorphic. The second proband was an 18-year-old girl who did not have dysmorphic features. Her deletion was also de novo, and she had a younger brother without the deletion who had autism. The third proband with a deletion inherited it from his affected mother. He had tall broad forehead with hypertelorism, midface hypoplasia, anteverted nares, smooth philtrum, wide mouth, and posteriorly rotated ears. His brother also carried the deletion and had similar facial features and autism. Their mother, who had mild mental retardation and autism, was brachycephalic with a receding hairline, deep-set eyes, smooth philtrum, large ears, and unusually short fifth toes. 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.
Wat et al. (2011) reported 2 unrelated patients with multiple congenital anomalies, but ascertained due to congenital diaphragmatic hernia (CDH), who each had a de novo interstitial deletion of 16p11.2. A 2-year-old boy with right-sided CDH, microretrognathia, cleft palate, right inguinal hernia, and paternally inherited autosomal dominant polydactyly had biallelic 554-kb and 982-kb deletions of chromosome 16p11.2 by real-time quantitative PCR. The other patient was a newborn infant with left-sided CDH, hypoplastic nonarticulating thumbs, extrathoracic vertebra, and 13 pairs of ribs, who died on the 17th day of life with severe respiratory insufficiency and pulmonary hypertension. He was found to have a 771-kb deletion by FISH analysis.
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 deletion patients had language delay and learning disabilities, and 1 met criteria for pervasive developmental disorder. Both deletion patients had symptomatic long cervicothoracic syringomyelia, 1 associated with Chiari I malformation and cerebellar tonsillar herniation, and the duplication patient had symptomatic long thoracolumbar syringomyelia. One of the deletion patients was obese. The minimal size of the rearrangement in all 3 patients was 579 kb.
Clinical Variability
Shiow et al. (2009) reported a girl with attention deficit-hyperactivity disorder and mild cognitive impairment associated with a de novo heterozygous 600-kb deletion of chromosome 16p11.2 encompassing 24 genes, including CORO1A (605000). In addition, she had T-, B+, NK+ severe combined immunodeficiency (SCID) characterized by early-onset recurrent infections and post-vaccination varicella at age 13 months. Immunologic workup showed decreased numbers of lymphocytes, poor T-cell function with decreased proliferative response and lack of helper T-cell function for antibody isotype switching, and low immunoglobulins. Her thymus was present. Hematopoietic stem cell transplantation was successful. Molecular studies excluded mutations in known SCID genes and identified a heterozygous 2-bp deletion in the CORO1A gene (605000.0001) that was inherited from the unaffected father. Thus, she had a homozygous absence of the CORO1A gene, with absent expression of the protein in her lymphocytes. Shiow et al. (2008) demonstrated that Coro1a is mutated in a mouse model with a peripheral T cell deficiency (Ptcd), providing further evidence for pathogenicity.
Association of the 593-kb Deletion Region with Obesity
Bochukova et al. (2010) noted that 4 patients carrying 750- to 780-kb deletions of chromosome 16p11.2, which included the 593-kb region, had developmental delay and/or autism and severe obesity and had been previously reported by Kumar et al. (2008), Weiss et al. (2008), or Marshall et al. (2008).
Walters et al. (2010) reported a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kb at chromosome 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from 8 European cohorts. These deletions were absent from healthy nonobese controls and accounted for 0.7% of morbid obesity cases (body mass index (BMI) greater than or equal to 40 kg/m(2), or BMI standard deviation score greater than or equal to 4.0; p = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with a strong effect.
Barnby et al. (2005) presented evidence for an autism susceptibility locus on chromosome 16p.
On the basis of screening copy number variants associated with autism, Sebat et al. (2007) detected a deletion of 16p11.2 associated with autism.
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.
Using array comparative genomic hybridization, Kumar et al. (2008) identified a recurrent 16p11.2 microdeletion in 4 (0.6%) of 712 probands with autism and 0 of 837 controls (p = 0.044). The deletion spanned approximately 500 kb and was flanked by approximately 147-kb segmental duplications, suggesting a recombination mechanism. Family analysis showed that 1 of the patients had an affected sib with the microdeletion; however, the 3 other probands each had an affected sib who did not carry the microdeletion. These latter 3 probands all had de novo mutations, whereas the 2 sibs apparently inherited the deletion from their unaffected father, who was presumably mosaic for the deletion. There were no striking phenotypic characteristics to distinguish the patients with the microdeletion. Kumar et al. (2008) suggested that the 16p11.2 microdeletion may be a risk factor for the development of autism.
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.
Bijlsma et al. (2009) found a recurrent approximately 600-kb deletion of chromosome 16p11.2 in 14 (0.3%) of 4,284 probands with mental retardation/multiple congenital anomalies. Six cases were de novo, and 6 were inherited from parents with a milder or normal phenotype; the last 2 cases could not be assessed. Though some patients shared a mildly dysmorphic facial appearance and a tendency to be overweight, there was no evidence for a recognizable phenotype. Twelve of 14 had developmental delay ranging from motor retardation to severe mental retardation, and 10 had speech problems, but autism was formally diagnosed only in 1 patient. Three apparently normal parents also carried the deletion. A father and son had an atypical 205-kb deletion of chromosome 16p11.2. Bijlsma et al. (2009) concluded that recurrent 16p11.2 deletions are associated with a variable clinical outcome, but that the phenotypic spectrum can range from mental retardation and/or multiple congenital anomalies to autism, learning and speech problems, to a normal phenotype.
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 composed 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. Sahoo et al. (2011) identified the 16p11.2 microdeletion in 98 individuals; 27 were de novo, 10 maternally inherited, none paternally inherited, and 61 of unknown inheritance. The average age at diagnosis was 8.9 years with an age range of 0.3 to 31.8 years, and the indications for study included developmental delay, speech and language delay, behavioral problems, autism, autism spectrum disorders, dysmorphic features, and seizures. The microdeletion was seen in 98 of 23,250 cases referred to their laboratory for a frequency of 0.42%, and in 3 of 5,674 controls for a frequency of 0.05% and a p value of less than 0.0001 (Itsara et al., 2009). In a case-control comparison in schizophrenia populations the microdeletion was seen at an equal frequency among cases and controls (0.03%; McCarthy et al., 2009), but in a case-control comparison in a variable neurodevelopmental deficit population was seen in 0.78% of cases versus 0.02% of controls (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. Only five 16p11.2 deletions were found among the control population, providing strong evidence for the pathogenic nature of this CNV (OR, 8.64; p = 6.34(-10)).
Crepel et al. (2011) identified an approximately 118-kb deletion within 16p11.2 that segregated with ASD and other neurodevelopmental abnormalities in a single 3-generation pedigree. This deletion encompassed 5 genes, including KCTD13 (608947). Golzio et al. (2012) performed an MLPA assay of this restricted region in 518 subjects that met diagnostic criteria for autism or ASD and found full-segment deletions in 8 independent ASD subjects (1.54%; 6 deletions and 2 duplications), compared to just 5 such events from 8,328 controls (0.06%). One proband with a narrow diagnosis of autism had a deletion only of exon 4 of KCTD13.
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 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.
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