Copy number variation and mosaicism

Notini, Amanda J.; Craig, Jeffrey M; White, Stefan J.

doi:10.1159/000184717

Cited by 50 publications

(40 citation statements)

References 98 publications

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“…Side-by-side comparison these two cases 83350 (father) and 83349 (daughter) showed identical breakpoint regions and the expected differences between the hemizygous and mosaic state (Figure 2). Similar mosaic genomic changes somatic or somatic and germline mosaicism have been reported in Duchenne Muscular Dystrophy, Neurofibromatosis 1 and 2 and other skin, blood and neuromuscular disorders, reviewed by Notini et al and Erickson (Erickson, 2010;Notini et al, 2008). For the first time, we showed that the existence of mosaic mutations (large deletions) may play a significant role in the development of MO in patients who are negative for mutations in Exostosins when analyzed by sequencing and MLPA.…”

Section: Discussionsupporting

confidence: 84%

Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients

et al. 2010

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Multiple osteochondromas (MO) is a hereditary skeletal disorder characterized by the presence of cartilage capped bony outgrowths at bone surface. Causative mutations in EXT1 or EXT2 genes have been described in 85-90 % of MO cases. However, in about 10-15 % of the MO cases, genomic alterations can not be detected, implying the potential role of other alterations. We have designed a custom-made Agilent oligonucleotide-based microarray, containing 44,000 probes, with tiling coverage of EXT1/2 genes and addition of 68 genes involved in heparan sulfate biosynthesis and other related pathways. Out of the 17 patient samples with previously undetected mutations, a low level of deletion of the EXT1 gene in about 10-15% of the blood cells was detected in two patients and mosaic deletion of the EXT2 was detected in one patient. Here we show that for the first time somatic mosaicism with large genomic deletions as the underlying mechanism in MO formation was identified. We propose that the existence of mosaic mutations and not alterations of other heparan sulfate biosynthesis related genes play a significant role in the development of MO in patients who are tested negative for mutations in Exostosins.

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Section: Discussionsupporting

confidence: 84%

Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients

et al. 2010

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“…Application of nextgeneration sequencing methods will allow for an easier and more sensitive calling of the smallest mosaic aberrations in the near future and will add up to the (scarce) data generated recently on this topic by some other groups. [30][31][32][33] Various causes could account for the discrepancy in CNV findings between our congenital anomaly twin cohort and the Parkinson's cohort. First of all, an age factor: the rather high prevalence of mosaic CNVs in PD twins could have been generated during lifetime.…”

Section: Discussionmentioning

confidence: 78%

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

et al. 2011

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The occurrence of phenotypic differences between monozygotic (MZ) twins is commonly attributed to environmental factors, assuming that MZ twins have a complete identical genetic make-up. Yet, recently several lines of evidence showed that both genetic and epigenetic factors could have a role in phenotypic discordance after all. A high occurrence of copy number variation (CNV) differences was observed within MZ twin pairs discordant for Parkinson's disease, thereby stressing on the importance of post-zygotic mutations as disease-predisposing events. In this study, the prevalence of discrepant CNVs was analyzed in discordant MZ twins of the Esophageal Atresia (EA) and Congenital Diaphragmatic Hernia (CDH) cohort in the Netherlands. Blood-derived DNA from 11 pairs (7 EA and 4 CDH) was screened using high-resolution SNP arrays. Results showed an identical copy number profile in each twin pair. Mosaic chromosome gain or losses could not be detected either with a detection threshold of 20%. Some of the germ-line structural events demonstrated in five out of eleven twin pairs could function as a susceptible genetic background. For example, the 177-Kb loss of chromosome 10q26 in CDH pair-3 harbors the TCF7L2 gene (Tcf4 protein), which is implicated in the regulation of muscle fiber type development and maturation. In conclusion, discrepant CNVs are not a common cause of twin discordancy in these investigated congenital anomaly cohorts.

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“…11 The clinical history of the mother included a relatively late menarche (16 years) with irregular menstruation up to the first pregnancy. Before this pregnancy she had received hormonal stimulation, but this was stopped before conception.…”

Section: Resultsmentioning

confidence: 99%

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

et al. 2011

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Disorders of sex development (DSD) are congenital conditions where chromosomal, gonad or genital development is atypical. In a significant proportion of 46,XY DSD cases it is not possible to identify a causative mutation, making genetic counseling difficult and potentially hindering optimal treatment. Here, we describe the analysis of a 46,XY DSD patient that presented at birth with ambiguous genitalia. Histological analysis of the surgically removed gonads showed bilateral undifferentiated gonadal tissue and immature testis, both containing malignant germ cells. We screened genomic DNA from this patient for deletions and duplications using an Illumina whole-genome SNP microarray. This analysis revealed a heterozygous deletion within the WWOX gene on chromosome 16, removing exons 6-8. Analysis of parental DNA showed that the deletion was inherited from the mother. cDNA analysis confirmed that the deletion maintained the reading frame, with exon 5 being spliced directly onto exon 9. This deletion is the first description of a germline rearrangement affecting the coding sequence of WWOX in humans. Previously described Wwox knockout mouse models showed gonadal abnormalities, supporting a role for WWOX in human gonad development. Keywords: disorders of sex development; copy number; WWOX; gonad; microarrays INTRODUCTIONIn the early stages of human embryogenesis the developing gonads are bipotent, being capable of forming either testes or ovaries. In males the expression of the Y chromosomal SRY gene initiates testis development, whereas ovarian development in principle occurs only in the absence of SRY (reviewed in Wilhelm et al 1 ). Following the establishment of sex-specific expression of key regulatory genes in the gonad, gonadal differentiation results in development of the external genitalia. As a result there are two main stages in gonad formation, and disruption of either can lead to disorders of sex development (DSD). DSD are surprisingly common, with ambiguous genitalia estimated to occur with an incidence of 1 in 4500 live births. 2 A number of genes important in the regulation of sex determination have been identified, yet in as many as 70% of 46,XY DSD cases no genetic cause has been identified. We have previously demonstrated the power of whole-genome copy number analysis with high-density microarrays to identify causative mutations in DSD. 3,4 Here, we describe the use of this approach to identify a multi-exon heterozygous deletion in the WWOX gene of a 46,XY DSD patient.

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Copy number variation and mosaicism

Cited by 50 publications

References 98 publications

Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients

Tiling resolution array-CGH shows that somatic mosaic deletion of the EXT gene is causative in EXT gene mutation negative multiple osteochondromas patients

Copy number detection in discordant monozygotic twins of Congenital Diaphragmatic Hernia (CDH) and Esophageal Atresia (EA) cohorts

A multi-exon deletion within WWOX is associated with a 46,XY disorder of sex development

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