M-banding characterization of a 16p11.2p13.1 tandem duplication in a child with autism, neurodevelopmental delay and dysmorphism

Behjati, Farkhondeh; Shafaghati, Yousef; Firouzabadi, Saghar Ghasemi; Kahrizi, Kimia; Bagherizadeh, Iman; Najmabadi, Hossein; Bint, Susan; Ogilvie, Caroline Mackie

doi:10.1016/j.ejmg.2008.06.007

Cited by 13 publications

(8 citation statements)

References 17 publications

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“…30 However, other reports associated this CNV with a variety of neuropsychiatric and neurobehavioral disorders, including autism, schizophrenia, intellectual disabilities, cognitive impairment, attention deficit hyperactivity disorder, and epilepsy, as well as congenital heart defects, skeletal manifestations, and thoracic aortic aneurysms and dissections. [31][32][33][34][35][36][37] We suggest that this duplication may contribute to the autistic features seen in patient 7.…”

Section: Discussionmentioning

confidence: 71%

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

Wiśniowiecka‐Kowalnik¹,

Kastory-Bronowska

Bartnik³

et al. 2012

Eur J Hum Genet

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Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders, including childhood autism, atypical autism, and Asperger syndrome, with an estimated prevalence of 1.0-2.5% in the general population. ASDs have a complex multifactorial etiology, with genetic causes being recognized in only 10-20% of cases. Recently, copy-number variants (CNVs) have been shown to contribute to over 10% of ASD cases. We have applied a custom-designed oligonucleotide array comparative genomic hybridization with an exonic coverage of over 1700 genes, including 221 genes known to cause autism and autism candidate genes, in a cohort of 145 patients with ASDs. The patients were classified according to ICD-10 standards and the Childhood Autism Rating Scale protocol into three groups consisting of 45 individuals with and 69 individuals without developmental delay/intellectual disability (DD/ID), and 31 patients, in whom DD/ID could not be excluded. In 12 patients, we have identified 16 copy-number changes, eight (5.5%) of which likely contribute to ASDs. In addition to known recurrent CNVs such as deletions 15q11.2 (BP1-BP2) and 3q13.31 (including DRD3 and ZBTB20), and duplications 15q13.3 and 16p13.11, our analysis revealed two novel genes clinically relevant for ASDs: ARHGAP24 (4q21.23q21.3) and SLC16A7 (12q14.1). Our results further confirm the diagnostic importance of array CGH in detection of CNVs in patients with ASDs and demonstrate that CNVs are an important cause of ASDs as a heterogeneous condition with a variety of contributory genes.

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Section: Discussionmentioning

confidence: 71%

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

Wiśniowiecka‐Kowalnik¹,

Kastory-Bronowska

Bartnik³

et al. 2012

Eur J Hum Genet

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“…From centromere to telomere, these include first, the common microdeletions/duplications of B600 kb in 16p11.2 associated with neurocognitive difficulties and obesity; [2][3][4] second, the microscopically visible duplications of 8-9 Mb from 16p11.2 to 16p12.1/2 associated with developmental delay and autism [5][6][7][8][9][10][11] and the reciprocal microdeletions associated with developmental delay, intellectual disability and subtle dysmorphic features; 12,13 within these are, third, the distal (formerly atypical) microdeletions of B220 kb in 16p11.2 associated with a phenotype that includes developmental delay or obesity but extends into the normal range [14][15][16] and, fourth, the microdeletions/duplications of B520 kb in 16p12.1 associated with developmental delay. 1, 17 Here, we report two new patients with cytogenetically visible duplications of 16p11.2-16p12.2 analysed using oligonucleotide array comparative genomic hybridisation (oaCGH) and compared with 10 previous postnatal patients.…”

Section: Introductionmentioning

confidence: 99%

“…1, 17 Here, we report two new patients with cytogenetically visible duplications of 16p11.2-16p12.2 analysed using oligonucleotide array comparative genomic hybridisation (oaCGH) and compared with 10 previous postnatal patients. [5][6][7][8][9][10][11] CNV is common with over 66 000 examples recorded in the Database of Genomic Variants (DGV) and an estimated 1% of the human population having a CNV 41 Mb. 1 When copy number is high enough, rare CNVs of 8p23.1, 9p12, 9qh/q12, 9q13, 15q11.2 and 16p11.2 become visible in the light microscope and have been described as euchromatic variants.…”

Section: Introductionmentioning

confidence: 99%

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

et al. 2012

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Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.

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“…All five genes have been described in conditions that demonstrate disease resulting from haploinsufficiency or loss of function of the gene product, so it is unclear whether triplication of these genes contribute to our patients' phenotypes. Evidence for dosage-sensitive genes in the 16p11.2-12.2 region is supported by previous reports of duplications associated with phenotypes including developmental delay, dysmorphic features, intellectual disability, autism spectrum disorder, microcephaly, short stature, and tapered fingers [Finelli et al, 2004;Behjati et al, 2008;Bourthoumieu et al, 2008;Tabet et al, 2012;Barber et al, 2013].…”

Section: Discussionmentioning

confidence: 70%

“…Of these, the most common is the 550 kb microdeletion at 16p11.2 that is estimated to be present in 1% of patients with autism spectrum disorder (ASD) [Weiss et al, 2008]. Duplications involving 16p11.1p13.1 [Kirchhoff et al, 2005], 16p11.2p12.1 [Engelen et al, 2002;Bourthoumieu et al, 2008], 16p11.2p12.2 [Finelli et al, 2004;Pani et al, 2010;Tabet et al, 2012;Barber et al, 2013], 16p11.2p13.1 [Behjati et al, 2008], 16p12.1p12.2 [Ballif et al, 2007], and 16p12.2 [Marshall et al, 2008;Itsara et al, 2009] have also been reported in association with neurodevelopmental disorders, congenital anomalies, and dysmorphic features, suggesting that a number of dosage-sensitive genes reside in that region. There is a single report of triplication involving 16p12.1 in a patient with intellectual disability, dysmorphic facial features, short stature, and hypotonia [Ballif et al, 2007].…”

Section: Introductionmentioning

confidence: 98%

Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features

Nimmo

Guerin

Badilla‐Porras

et al. 2015

American J of Med Genetics Pt A

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The 16p12 region is particularly prone to genomic disorders due to the large number of low copy repeats [Martin et al., 2004; Nature 432:988-994]. We report two unrelated patients with de novo triplication of 16p12.1p12.3 who had developmental delay and similar facial features. Patient 1 is a 4-year-old male with a congenital heart anomaly, bilateral cryptorchidism, chronic constipation, and developmental delay. Patient 2 is a 12-year-old female with prenatally diagnosed hydronephrosis, hepatobiliary disease, failure to thrive, and developmental delay. Distinctive facial features common to both patients include short palpebral fissures, bulbous nose, thin upper vermillion border, apparently lowset ears, and large ear lobes. We compare the clinical manifestations of our patients with a previously reported patient with triplication of 16p12.2.

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M-banding characterization of a 16p11.2p13.1 tandem duplication in a child with autism, neurodevelopmental delay and dysmorphism

Cited by 13 publications

References 17 publications

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

16p11.2–p12.2 duplication syndrome; a genomic condition differentiated from euchromatic variation of 16p11.2

Triplication of 16p12.1p12.3 associated with developmental and growth delay and distinctive facial features

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