Copy Number Variants, Aneuploidies, and Human Disease

Martin, Christa Lese; Kirkpatrick, Brianne; Ledbetter, David H.

doi:10.1016/j.clp.2015.03.001

Cited by 56 publications

(57 citation statements)

References 41 publications

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“…Consequently, the identification of an underlying genetic etiology in patients with ID, ASD and MCA has significantly increased due to the application of CNV microarrays [20,71]. The impact of establishing a genetic diagnosis in congenital disorders is significant as it allows appropriate referrals for therapy, surveillance for potential future involvement of other tissues and organs and assist in better genetic counseling for the family [65].…”

Section: The Evolution Of Cnv Detection Methodsmentioning

confidence: 99%

“…CNV analysis with microarrays is offered as routine clinical test, with the results being increasingly used in genetic counseling and clinical management [71]. However, the ability to detect CNVs using high throughput technologies has far outpaced the ability to determine their role in disease pathogenesis.…”

Section: Challenges In Cnv Association To Diseasementioning

confidence: 99%

“…This is mainly because the interpretation of novel CNVs is difficult, leading to wide variability in assessment and reporting of the clinical significance of CNVs by different diagnostic laboratories [65]. Some guidelines that allow better interpretation of the clinical significance or disease association of CNVs include criteria such as, overlap with known contiguous gene syndromes; CNV size and gene content; whether the CNV is de novo or inherited; comparison to CNV databases and medical literature [71]. …”

Section: Challenges In Cnv Association To Diseasementioning

confidence: 99%

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Copy Number Variation Disorders

Shaikh

2017

Curr Genet Med Rep

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Purpose of Review Copy number variation (CNV) disorders arise from the dosage imbalance of one or more gene(s), resulting from deletions, duplications or other genomic rearrangements that lead to the loss or gain of genetic material. Several disorders, characterized by multiple birth defects and neurodevelopmental abnormalities, have been associated with relatively large (>1 Mb) and often recurrent CNVs. CNVs have also been implicated in the etiology of neuropsychiatric disorders including autism and schizophrenia as well as other common complex diseases. Thus, CNVs have a significant impact on human health and disease. Recent Findings The use of increasingly higher resolution, genomewide analysis has greatly enhanced the detection of genetic variation, including CNVs. Furthermore, the availability of comprehensive genetic variation data from large cohorts of healthy controls has the potential to greatly improve the identification of disease associated genetic variants in patient samples. Summary This review discusses the current knowledge about CNV disorders, including the mechanisms underlying their formation and phenotypic outcomes, and the advantages and limitations of current methods of detection and disease association.

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Section: The Evolution Of Cnv Detection Methodsmentioning

confidence: 99%

Section: Challenges In Cnv Association To Diseasementioning

confidence: 99%

Section: Challenges In Cnv Association To Diseasementioning

confidence: 99%

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Copy Number Variation Disorders

Shaikh

2017

Curr Genet Med Rep

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“…CMA's increased yield over traditional karyotyping (Crolla et al 2014; Wapner et al, 2012) led the American College of Obstetrics and Gynecology (ACOG) to recommend prenatal CMA testing be considered a first tier test following detection of an ultrasound anomaly, and made available when performing invasive genetic testing for any indication including maternal age (American College of Obstetricians and Gynecologist 2013). The increased diagnostic yield of CMA is, however, accompanied by the possibility of finding CNVs of uncertain clinical significance (VUS), incomplete penetrance, or variable expressivity (Martin et al 2015) with a wide range of associated phenotypes ranging from apparently normal to severely affected.…”

Section: Introductionmentioning

confidence: 99%

“Something Extra on Chromosome 5”: Parents’ Understanding of Positive Prenatal Chromosomal Microarray Analysis (CMA) Results

Walser

Werner‐Lin

Russell

et al. 2016

Journal of Genetic Counseling

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This study aims to explore how couples’ understanding of the nature and consequences of positive prenatal chromosomal microarray analysis (CMA) results impacts decision-making and concern about pregnancy. We interviewed 28 women and 12 male partners after receiving positive results and analyzed the transcripts to assess their understanding and level of concern about the expected clinical implications of results. Participant descriptions were compared to the original laboratory interpretation. When diagnosed prenatally, couples’ understanding of the nature and consequences of copy number variants (CNVs) impacts decision-making and concern. Findings suggest women, but less so partners, generally understand the nature and clinical implications of prenatal CMA results. Couples feel reassured, perhaps sometimes falsely so, when a CNV is inherited from a “normal” parent and experience considerable uncertainty when a CNV is de novo, frequently precipitating a search for additional information and guidance. Five factors influenced participants’ concern including: the pattern of inheritance, type of possible phenotypic involvement, perceived manageability of outcomes, availability and strength of evidence about outcomes associated with the CNV, and provider messages about continuing the pregnancy. A good understanding of results is vital as couples decide whether or not to continue with their pregnancy and seek additional information to assist in pregnancy decision-making.

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“…For example, copynumber variants resulting from the reciprocal deletion and duplication products of nonallelic recombination are associated with dozens of recurrent human disorders (Stankiewicz and Lupski 2002;Shaw and Lupski 2004;Sharp et al 2005;Turner et al 2008;Abyzov et al 2015;Martin et al 2015). These include hereditary neuropathy with liability to pressure palsies and Charcot-Marie -Tooth disease type 1A (Chance et al 1994), Prader-Willi syndrome/ Angelman syndrome and 15q11q13 duplication (Long et al 1998), velocardiofacial syndrome and dup22(q11.2q11.2) (Edelmann et al 1999a), Smith -Magenis syndrome and Potocki -Lupski syndrome (Potocki et al 2000), and Williams -Beuren syndrome and dup7 (q11.23) (Somerville et al 2005).…”

Section: Meiotic Recombination and Genomic Disordersmentioning

confidence: 99%

Meiotic Recombination: The Essence of Heredity

Hunter

2015

Cold Spring Harb Perspect Biol

673

869

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The study of homologous recombination has its historical roots in meiosis. In this context, recombination occurs as a programmed event that culminates in the formation of crossovers, which are essential for accurate chromosome segregation and create new combinations of parental alleles. Thus, meiotic recombination underlies both the independent assortment of parental chromosomes and genetic linkage. This review highlights the features of meiotic recombination that distinguish it from recombinational repair in somatic cells, and how the molecular processes of meiotic recombination are embedded and interdependent with the chromosome structures that characterize meiotic prophase. A more in-depth review presents our understanding of how crossover and noncrossover pathways of meiotic recombination are differentiated and regulated. The final section of this review summarizes the studies that have defined defective recombination as a leading cause of pregnancy loss and congenital disease in humans. MEIOSIS AND THE ROOTS OF RECOMBINATION RESEARCHT he concept of recombination emerged during the early 20th century, following the post-Mendel era of heredity research. Thomas Hunt Morgan's formal theory of gene linkage and crossing-over (Morgan 1913) was a synthesis of three key concepts: "the chromosome theory of inheritance," imparted by Wilhelm Roux, Walther Flemming, Theodor Boveri, and Walter Sutton; "gene linkage," an exception to Mendel's law of independent assortment, first reported by Carl Correns; and the "chiasmatype theory," derived from Frans Janssens' cytological observations of meiotic chromosomes. The first proof of the crossover theory came from Harriet Creighton and Barbara McClintock (Creighton and McClintock 1931), who were able to correlate cytological and genetic exchanges in maize.Experiments aimed at understanding the mechanism of meiotic recombination became dominated by fungal genetics because of the huge advantage afforded by being able to recover all four meiotic products. These elegant studies culminated in four key concepts that formed the foundation of molecular models of recombination: gene conversion, an exception to Mendel's principle of segregation, signaled a local nonreciprocal transfer of genetic information (Winkler 1930;Lindergren 1953;Mitchell 1955); postmeiotic segregation (PMS) indicated the presence of heteroduplex DNA (Olive 1959;Kitani et al. 1962) (Lissouba and Rizet 1960;Murray 1960); and the strong correlation between gene conversion/ PMS events and crossing-over led to the proposal that these processes were mechanistically linked (Kitani et al. 1962;Perkins 1962;Whitehouse 1963). MOLECULAR MODELS OF MEIOTIC RECOMBINATIONHolliday's classic model reconciled gene conversion, PMS, and crossing-over into a single mechanism with the key features of hybrid (heteroduplex) DNA formed via strand exchange, mismatch correction of hybrid DNA to yield gene conversion, and a four-way exchange junction that could be resolved to yield either crossover or noncrossover duplex products (Holliday...

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Copy Number Variants, Aneuploidies, and Human Disease

Cited by 56 publications

References 41 publications

Copy Number Variation Disorders

Copy Number Variation Disorders

“Something Extra on Chromosome 5”: Parents’ Understanding of Positive Prenatal Chromosomal Microarray Analysis (CMA) Results

Meiotic Recombination: The Essence of Heredity

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