Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice

Bruno, Damien L.; Ganesamoorthy, Devika; Schoumans, Jacqueline; Bankier, Agnes; Coman, David; Delatycki, Martin B.; Gardner, R. J. M.; Hunter, Matthew F.; James, Philip; Kannu, Peter; McGillivray, George; Pachter, Nicholas; Peters, Heather; Rieubland, Claudine; Savarirayan, Ravi; Scheffer, Ingrid E.; Sheffield, Leslie J.; Tan, Tiong Yang; White, Stuart; Yeung, Alison; Bowman, Z; Ngo, Con; Choy, Kwong Wai; Cacheux, V; Wong, Lee H.; Amor, David J.; Slater, HR

doi:10.1136/jmg.2008.062604

Cited by 67 publications

(49 citation statements)

References 39 publications

(29 reference statements)

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“…pathogenic CNVs are mostly 4500 kb). 21 As expected, microarray analyses of patient 53B also revealed known CNVs in other parts of his genome (data not shown).…”

Section: Identification and Characterization Of Breakpointsmentioning

confidence: 72%

Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

et al. 2010

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Aortic dilatation/dissection (AD) can occur spontaneously or in association with genetic syndromes, such as Marfan syndrome (MFS; caused by FBN1 mutations), MFS type 2 and Loeys-Dietz syndrome (associated with TGFBR1/TGFBR2 mutations), and Ehlers-Danlos syndrome (EDS) vascular type (caused by COL3A1 mutations). Although mutations in FBN1 and TGFBR1/ TGFBR2 account for the majority of AD cases referred to us for molecular genetic testing, we have obtained negative results for these genes in a large cohort of AD patients, suggesting the involvement of additional genes or acquired factors. In this study we assessed the effect of COL3A1 deletions/duplications in this cohort. Multiplex ligation-dependent probe amplification (MLPA) analysis of 100 unrelated patients identified one hemizygous deletion of the entire COL3A1 gene. Subsequent microarray analyses and sequencing of breakpoints revealed the deletion size of 3 408 306 bp at 2q32.1q32.3. This deletion affects not only COL3A1 but also 21 other known genes (GULP1, DIRC1, COL5A2, WDR75, SLC40A1, ASNSD1, ANKAR, OSGEPL1, ORMDL1, LOC100129592, PMS1, MSTN, C2orf88, HIBCH, INPP1, MFSD6, TMEM194B, NAB1, GLS, STAT1, and STAT4), mutations in three of which (COL5A2, SLC40A1, and MSTN) have also been associated with an autosomal dominant disorder (EDS classical type, hemochromatosis type 4, and muscle hypertrophy). Physical and laboratory examinations revealed that true haploinsufficiency of COL3A1, COL5A2, and MSTN, but not that of SLC40A1, leads to a clinical phenotype. Our data not only emphasize the impact/role of COL3A1 in AD patients but also extend the molecular etiology of several disorders by providing hitherto unreported evidence for true haploinsufficiency of the underlying gene.

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“…pathogenic CNVs are mostly 4500 kb). 21 As expected, microarray analyses of patient 53B also revealed known CNVs in other parts of his genome (data not shown).…”

Section: Identification and Characterization Of Breakpointsmentioning

confidence: 72%

Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

et al. 2010

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“…6,7 Information about ROH may also be useful for the discovery of new syndromes. 16,17 Although the detection of ROH may be clinically useful for diagnosis, it also has the potential to raise significant legal and ethical concerns. Discovery of a parental consanguineous or incestuous relationship (a blood relationship between the parents of the proband) by SNP microarray may come as a surprise to the laboratory, the ordering physician, and even to the family.…”

Section: Introductionmentioning

confidence: 99%

Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing

Grote

Myers

Lovell

et al. 2012

Genetics in Medicine

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Purpose: Single-nucleotide polymorphism (SNP) microarrays are capable of detecting regions of homozygosity (ROH) that can suggest parental consanguinity or incest. This study was designed to describe the variable reporting practices of clinical laboratories in the United States regarding ROH found on SNP microarray tests, to discuss the follow-up practices of laboratory personnel when findings of ROH indicate consanguinity or incest, and to highlight the legal and ethical dilemmas faced by workers who have discovered these incidental findings.methods: A 20-question survey was administered to microarray experts at 18 laboratories offering clinical SNP microarray tests. The results are presented using descriptive statistics.results: There was variability in laboratory SNP microarray reporting practices with respect to information and interpretation of ROH findings. All the laboratories agreed that they have a duty to inform the ordering physician about results suggesting consanguinity or incest, but the follow-through practices varied among laboratories.conclusions: This study discovered variability in reporting practices and follow-up procedures for microarray results that suggest parental consanguinity or incest. Our findings highlight the need for laboratory guidelines to standardize reporting practices for SNP microarray and other tests that are capable of detecting ROH. 2012:14(12):971-976 Genet Med

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“…The scheme is partly based on previously published studies, [8][9][10][11] but did not include origin or size as possible exclusion criterium, as these were subject of our study in the first cohort. We assessed the gains of this cohort using the following steps:…”

Section: Interpretation Of Gainsmentioning

confidence: 99%

“…[8][9][10][11] These studies included both copy number losses and gains. Koolen et al 8 stated in their interpretation workflow that if a CNV is familial, it is likely not to be clinically relevant.…”

Section: Introductionmentioning

confidence: 99%

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics

et al. 2011

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The correct interpretation of copy number gains in patients with developmental delay and multiple congenital anomalies is hampered by the large number of copy number variations (CNVs) encountered in healthy individuals. The variable phenotype associated with copy number gains makes interpretation even more difficult. Literature shows that inheritence, size and presence in healthy individuals are commonly used to decide whether a certain copy number gain is pathogenic, but no general consensus has been established. We aimed to develop guidelines for interpreting gains detected by array analysis using array CGH data of 300 patients analysed with the 105K Agilent oligo array in a diagnostic setting. We evaluated the guidelines in a second, independent, cohort of 300 patients. In the first 300 patients 797 gains of four or more adjacent oligonucleotides were observed. Of these, 45.4% were de novo and 54.6% were familial. In total, 94.8% of all de novo gains and 87.1% of all familial gains were concluded to be benign CNVs. Clinically relevant gains ranged from 288 to 7912 kb in size, and were significantly larger than benign gains and gains of unknown clinical relevance (Po0.001). Our study showed that a threshold of 200 kb is acceptable in a clinical setting, whereas heritability does not exclude a pathogenic nature of a gain. Evaluation of the guidelines in the second cohort of 300 patients revealed that the interpretation guidelines were clear, easy to follow and efficient.

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Detection of cryptic pathogenic copy number variations and constitutional loss of heterozygosity using high resolution SNP microarray analysis in 117 patients referred for cytogenetic analysis and impact on clinical practice

Cited by 67 publications

References 39 publications

Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

Hemizygous deletion of COL3A1, COL5A2, and MSTN causes a complex phenotype with aortic dissection: a lesson for and from true haploinsufficiency

Variability in laboratory reporting practices for regions of homozygosity indicating parental relatedness as identified by SNP microarray testing

Practical guidelines for interpreting copy number gains detected by high-resolution array in routine diagnostics

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