High resolution genomic analysis of 18q− using oligo‐microarray comparative genomic hybridization (aCGH)

Heard, Patricia; Carter, Erika M.; Crandall, AnaLisa C.; Sebold, Courtney; Hale, Daniel E.; Cody, Jannine D.

doi:10.1002/ajmg.a.32900

Cited by 51 publications

(65 citation statements)

References 19 publications

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“…Recurrent mutations have been observed in exon 18. The deletions are each unique and no clustering of breakpoints has been observed, which is in accordance with what is known of 18q deletions in general [Heard et al, 2009;Hasi et al, 2011].…”

Section: Mutation Spectrum and Genotype-phenotype Correlationsupporting

confidence: 88%

Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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a Pitt-Hopkins-like phenotype has been assigned to autosomal recessive mutations of the CNTNAP2 gene at 7q33q36 and the NRXN1 gene at 2p16.3. Copyright © 2011 S. Karger AG, Basel History of the SyndromeIn 1978, pediatrician David Pitt and pediatric neurologist Ian Hopkins at the Royal Children's Hospital in Melbourne described 2 unrelated children with severe intellectual disability who while awake had spells of rapid overbreathing followed by holding of breath until cyanosis [Pitt and Hopkins, 1978]. Both patients had almost identical facial features with a wide mouth and palate, thick fleshy lips and a broad beaked nose with flared nostrils, and both also had clubbing of fingers and toes. The patients had been ascertained as a part of an etiological survey of 782 intellectually disabled individuals [Pitt and Roboz, 1965]. Over the next 28 years, only 4 sporadic patients [Singh 1993;Van Balkom et al., 1998;Peippo et al., 2006] and 1 pair of sibs [Orrico et al., 2001] supposed to have the same syndrome were published.In 2007, 2 independent groups using molecular karyotyping identified a microdeletion at 18q21.2 in 2 PittHopkins syndrome (PTHS) patients and subsequently haploinsufficiency of the TCF4 gene was found to cause the syndrome [Amiel et al., 2007;Zweier et al., 2007]. The original patients of Pitt and Hopkins [1978] and the one described by Singh [1993] were no longer available for Key WordsApnea ؒ Constipation ؒ Deletion of 18q ؒ Epilepsy ؒ Happy disposition ؒ Hyperpnea ؒ Myopia ؒ Pitt-Hopkins syndrome ؒ Stereotypic movements ؒ TCF4 Abstract Pitt-Hopkins syndrome (PTHS, MIM #610954) is characterized by severe intellectual disability, typical facial features and tendency to epilepsy, panting-and-holding breathing anomaly, stereotypic movements, constipation, and high myopia. Growth is normal or only mildly retarded, but half of the patients have postnatal microcephaly. Remarkably, congenital malformations are practically nonexistent. The cause of PTHS is de novo haploinsufficiency of the TCF4 gene (MIM * 602272) at 18q21.2. Altogether 78 PTHS patients with abnormalities of the TCF4 gene have been published since 2007 when the etiology of PTHS was revealed. In addition, 27 patients with 18q deletion encompassing the TCF4 gene but without given PTHS diagnosis have been published, and thus, the number of reported patients with a TCF4 abnormality exceeds 100. The mutational spectrum includes large chromosomal deletions encompassing the whole TCF4 gene, partial gene deletions, frameshift (including premature stop codon), nonsense, splice site, and missense mutations. So far, almost all patients have a private mutation and only 2 recurrent mutations are known. There is no evident genotype-phenotype correlation. No familial cases have been reported. Diagnosis of PTHS is based on the molecular confirmation of the characteristic clinical features. Recently,

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Section: Mutation Spectrum and Genotype-phenotype Correlationsupporting

confidence: 88%

Pitt-Hopkins Syndrome

Peippo

Ignatius

2011

Mol Syndromol

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“…These regions were never found to be hemizygous in the 260 individuals with molecularly characterized abnormalities. 2 Figure 1 shows a zoomed in view of band 18q21.2.…”

Section: Resultsmentioning

confidence: 99%

“…In our evaluation of more than 200 individuals with hemizygosity of Chromosome 18q, only two unrelated individuals have identical genomic aberrations. 1,2 In 2002, we reported that 72% of individuals with 18p deletions have breaks at the centromere. 3 However, array comparative genomic hybridization (aCGH) has revealed that even those with so-called "centromeric breaks" have breakpoints that fall into four groups with different genetic content (unpublished data).…”

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confidence: 99%

A gene dosage map of Chromosome 18: A map with clinical utility

Cody

Carter

Sebold

et al. 2009

Genetics in Medicine

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Purpose: Microarray technology has revolutionized the field of clinical genetics with the ability to detect very small copy number changes. However, challenges remain in linking genotype with phenotype. Our goal is to enable a clinical geneticist to align the molecular karyotype information from an individual patient with the annotated genomic content, so as to provide a clinical prognosis. Methods: We have combined data regarding copy number variations, microdeletion syndromes, and classical chromosome abnormalities, with the sparse but growing knowledge about the biological role of specific genes to create a genomic map of Chromosome 18 with clinical utility. Results: We have created a draft model of such a map, drawing from our longstanding interest in and data regarding the abnormalities of Chromosome 18. Conclusion: We have taken the first step toward creating a genomic map that can be used by the clinician in counseling and directing preventive or symptomatic care of individuals with Chromosome 18 abnormalities. Genet Med 2009:11(11):778 -782.

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“…About 1/40,000 babies are born with a deletion in chromosome 18q (Unique, The Rare Chromosome Disorder Support Group, http:// www.rarechromo.org). A group of over 290 individuals with a terminal or interstitial deletion of 18q was analyzed using aCGH, and no overlaps of the deleted regions were found [Heard et al, 2009]. More than half of 16 individuals of the previous group with terminal deletion of 18q, with a breakpoint upstream CDH7 , have delayed myelination of the brain, foot anomalies, atretic and stenotic ear canals, hypospadias in males, tapered fingers, flat midface, proximally placed thumbs, and congenital heart anomalies [Cody et al, 2014].…”

Section: Discussionmentioning

confidence: 99%

Complex Rearrangement Involving Three Chromosomes, Four Breakpoints and a 2.7-Mb Deletion in the 18q Segment Observed in a Girl with Mild Learning Difficulties

Kontodiou¹,

Daskalakis²,

Vetro

et al. 2015

Cytogenet Genome Res

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Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving 3 or more cytogenetic break events on 2 or more different chromosomes. Here, we report a 7-year-old girl referred to our unit because of mild dysmorphic facial features, mild learning difficulties together with very mild mental retardation. Standard cytogenetic banding analysis revealed a de novo CCR involving chromosomes 1, 2 and 18. Further molecular investigation with aCGH revealed a cryptic interstitial deletion of 2.7 Mb in 18q22.1, which does not elicit a significant clinical phenotype. FISH was performed to confirm both molecular and cytogenetic results.

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High resolution genomic analysis of 18q− using oligo‐microarray comparative genomic hybridization (aCGH)

Cited by 51 publications

References 19 publications

Pitt-Hopkins Syndrome

Pitt-Hopkins Syndrome

A gene dosage map of Chromosome 18: A map with clinical utility

Complex Rearrangement Involving Three Chromosomes, Four Breakpoints and a 2.7-Mb Deletion in the 18q Segment Observed in a Girl with Mild Learning Difficulties

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