Microdeletion and Microduplication Syndromes

Weise, Anja; Mrasek, Kristin; Klein, Elisabeth; Mulatinho, Milene; Llerena, Juan Clinton; Hardekopf, David; Pekova, Sona; Bhatt, Samarth; Kosyakova, Nadezda; Liehr, Thomas

doi:10.1369/0022155412440001

Cited by 140 publications

(115 citation statements)

References 30 publications

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“…13,15 For other disorders, deletions and duplications involving the same dosagesensitive genes result in significantly different clinical presentations, such as seen in Williams syndrome and chromosome 7q11.23 duplication syndrome. 13,16 From the current study, it appears that MBD5 falls into the former category of dosage-sensitive genes, but additional cases will need to be studied to determine if there are features which have not been identified or are underappreciated. The phenotypes observed in the microdeletion and microduplication syndrome are similar, with the 2q23.1 microduplication syndrome having a somewhat milder phenotype.…”

Section: Discussionmentioning

confidence: 95%

Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

et al. 2013

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Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.

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Section: Discussionmentioning

confidence: 95%

Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

et al. 2013

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“…It has been demonstrated that CNVs (i.e., deletions or duplications of chromosomal segments) have a strong relationship with genome variability and contiguous gene syndrome and might be responsible for several conditions associated with short stature [18]. In 2009, the American College of Medical Genetics published the first practice guideline for genetic evaluation of short stature, which includes the recommendation for CNV investigation in patients with proportional short stature and other physical or developmental defects with an unrecognized syndrome [4].…”

Section: Discussionmentioning

confidence: 99%

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

et al. 2017

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Background/Aims: Genetic imbalances are responsible for many cases of short stature of unknown etiology. This study aims to identify recurrent pathogenic copy number variants (CNVs) in patients with syndromic short stature of unknown cause. Methods: We selected 229 children with short stature and dysmorphic features, developmental delay, and/or intellectual disability, but without a recognized syndrome. All patients were evaluated by chromosomal microarray (array-based comparative genomic hybridization/single nucleotide polymorphism array). Additionally, we searched databases and previous studies to recover recurrent pathogenic CNVs associated with short stature. Results: We identified 32 pathogenic/probably pathogenic CNVs in 229 patients. By reviewing the literature, we selected 4 previous studies which evaluated CNVs in cohorts of patients with short stature. Taken together, there were 671 patients with short stature of unknown cause evaluated by chromosomal microarray. Pathogenic/probably pathogenic CNVs were identified in 87 patients (13%). Seven recurrent CNVs, 22q11.21, 15q26, 1p36.33, Xp22.33, 17p13.3, 1q21.1, 2q24.2, were observed. They are responsible for about 40% of all pathogenic/probably pathogenic genomic imbalances found in short stature patients of unknown cause. Conclusion: CNVs seem to play a significant role in patients with short stature. Chromosomal microarray should be used as a diagnostic tool for evaluation of growth disorders, especially for syndromic short stature of unknown cause.

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“…Patients carrying reciprocal microduplication at 5q35.2q35.3 have no clinical phenotype or have a milder phenotype than do patients with microdeletion of the same region (Kirchhoff et al, 2007;Weise et al, 2012). According to Orphanet Report Series (2016), the number of published cases of the 5q35 microduplication worldwide is 14.…”

Section: Introductionmentioning

confidence: 99%

A rare case of a boy with de novo microduplication at 5q35.2q35.3 from central Brazil

et al. 2017

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ABSTRACT. Genomic disorders are genetic diseases that are caused by rearrangements of chromosomal material via deletions, duplications, and inversions of unique genomic segments at specific regions. Such rearrangements could result from recurrent non-allelic homologous recombination between low copy repeats. In cases where the breakpoints flank the low copy repeats, deletion of chromosomal segments is often followed by reciprocal duplication. Variations in genomic copy number manifest differently, with duplication and deletions of the same genomic region showing opposite phenotypes. Sotos syndrome is caused by alterations in the dosage of NSD1 on human chromosome 5 by either deletions or mutations, such as microdeletion of 5q35.2q35.3. In general, patients carrying reciprocal microduplication at 5q35.2q35.3 present no clinical phenotype or milder phenotype than do patients with microdeletion at the same locus. We report the first case of 5q35.2q35.3 microduplication encompassing NSD1 in a patient from central Brazil. We identified a genomic imbalance corresponding to a de novo 0.45 Mb microduplication at 5q35.2q35.3 by chromosomal microarray analysis and study of lowcopy repeats. The proband had microduplication in the chromosomal region containing NSD1, which resulted in a Sotos syndrome reversed phenotype, and this duplication was associated with microcephaly, short stature, and developmental delay. Analysis of the genomic structure of the rearranged 5q35.2q35.3 chromosomal region revealed two major low-copy repeat families, which caused the recurrent rearrangements. Chromosomal microarray analysis is a potential tool to identify microrearrangements and guide medical diagnosis, which has to be followed by a non-directive genetic counseling approach to improve the quality of life of the patient.

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Microdeletion and Microduplication Syndromes

Cited by 140 publications

References 30 publications

Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder

Recurrent Copy Number Variants Associated with Syndromic Short Stature of Unknown Cause

A rare case of a boy with de novo microduplication at 5q35.2q35.3 from central Brazil

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