CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing

Innes, Josie; Reali, Lisa; Clayton‐Smith, Jill; Hall, Georgina; Lim, Derek; Burghel, George J.; French, Kim D.; Khan, Unzela; Walker, Daniel; Lalloo, Fiona; Evans, D. Gareth; McMullan, Dominic; Woodward, Emma R.

doi:10.1136/jmedgenet-2017-104892

Cited by 9 publications

(6 citation statements)

References 41 publications

(17 reference statements)

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“…Because studies of secondary findings have focused almost exclusively on SNVs or other sequence changes, 30,31 data on intragenic CNVs in the ACMG-listed genes provide useful complementary insight into disease-predisposing variants observable in healthy individuals. 32…”

Section: Discussionmentioning

confidence: 99%

Prevalence and properties of intragenic copy-number variation in Mendelian disease genes

Truty

Paul

Kennemer

et al. 2019

Genetics in Medicine

144

126

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PurposeWe investigated the frequencies and characteristics of intragenic copy-number variants (CNVs) in a deep sampling of disease genes associated with monogenic disorders.MethodsSubsets of 1507 genes were tested using next-generation sequencing to simultaneously detect sequence variants and CNVs in >143,000 individuals referred for genetic testing. We analyzed CNVs in gene panels for hereditary cancer syndromes and cardiovascular, neurological, or pediatric disorders.ResultsOur analysis identified 2844 intragenic CNVs in 384 clinically tested genes. CNVs were observed in 1.9% of the entire cohort but in a disproportionately high fraction (9.8%) of individuals with a clinically significant result. CNVs accounted for 4.7–35% of pathogenic variants, depending on clinical specialty. Distinct patterns existed among CNVs in terms of copy number, location, exons affected, clinical classification, and genes affected. Separately, analysis of de-identified data for 599 genes unrelated to the clinical phenotype yielded 4054 CNVs. Most of these CNVs were novel rare events, present as duplications, and enriched in genes associated with recessive disorders or lacking loss-of-function mutational mechanisms.ConclusionUniversal intragenic CNV analysis adds substantial clinical sensitivity to genetic testing. Clinically relevant CNVs have distinct properties that distinguish them from CNVs contributing to normal variation in human disease genes.

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Section: Discussionmentioning

confidence: 99%

Prevalence and properties of intragenic copy-number variation in Mendelian disease genes

Truty

Paul

Kennemer

et al. 2019

Genetics in Medicine

144

126

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“…Filtered CNVs were manually assessed to exclude artifacts. 61 For comparison of CNV frequencies, the 2-tailed chi square test was employed. See also Supplemental Methods for further details, including ddPCR protocol.…”

Section: Snv and Cnv Detectionmentioning

confidence: 99%

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Robak

Du²,

Yuan³

et al. 2019

Preprint

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Background: Parkinson's disease (PD) is a genetically heterogeneous condition; both single nucleotide variants (SNVs) and copy number variants (CNVs) are important genetic risk factors.We examined the utility of combining exome sequencing and genome-wide array-based comparative genomic hybridization (aCGH) for identification of PD genetic risk factors. Methods:We performed exome sequencing on 110 subjects with PD and a positive family history; 99 subjects were also evaluated using genome-wide aCGH. We interrogated exome sequencing and array comparative genomic hybridization data for pathogenic SNVs and CNVs at Mendelian PD gene loci. SNVs were confirmed via Sanger sequencing. CNVs were confirmed with custom-designed high-density aCGH, droplet digital PCR, and breakpoint sequencing. Results:Using exome sequencing, we discovered individuals with known pathogenic single nucleotide variants in GBA (p.E365K, p.T408M, p.N409S, p.L483P) and LRRK2 (p.R1441G and p.G2019S). Two subjects were each double heterozygotes for variants in GBA and LRRK2.Based on aCGH, we additionally discovered cases with an SNCA duplication and heterozygous intragenic GBA deletion. Five additional subjects harbored both SNVs (p.N52fs, p.T240M, p.P437L, p.W453*) and likely disrupting CNVs at the PARK2 locus, consistent with compound heterozygosity. In nearly all cases, breakpoint sequencing revealed microhomology, a mutational signature consistent with CNV formation due to DNA replication errors. Conclusions:Integrated exome sequencing and aCGH yielded a genetic diagnosis in 19.3% of our familial PD cohort. Our analyses highlight potential mechanisms for SNCA and PARK2 CNV formation, uncover multilocus pathogenic variation, and identify novel SNVs and CNVs for further investigation as potential PD risk alleles.

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“…In 2010, the ACMG recommended that chromosomal microarray analysis (CMA) be used as the first‐tier test in patients with neurodevelopmental disorders and/or congenital anomalies as whole‐genome arrays yield pathogenic CNVs in 15%–22% of affected individuals 8,9 . Importantly, these patients may harbor medically actionable dosage‐sensitive genes within the deleted or duplicated segments and are unlikely to be tested by exome/genome sequencing 10‐14 . Whole gene duplication or deletion CNVs can be responsible for up 80% of the molecular diagnoses involving dosage‐sensitive genes 15 .…”

Section: Introductionmentioning

confidence: 99%

“…8,9 Importantly, these patients may harbor medically actionable dosage-sensitive genes within the deleted or duplicated segments and are unlikely to be tested by exome/genome sequencing. [10][11][12][13][14] Whole gene duplication or deletion CNVs can be responsible for up 80% of the molecular diagnoses involving dosage-sensitive genes. 15 Relevantly, intragenic CNVs account for about 10% of disease-causing variants [16][17][18] and represent another type of finding that can be detected by CMA or clinical exome/genome sequencing in laboratories that have adopted copy number calling pipelines.…”

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confidence: 99%

Copy number alterations involving 59 ACMG‐recommended secondary findings genes

Yatsenko

Aarabi

et al. 2020

Clinical Genetics

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In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single-nucleotide variants (SNVs) are observed in one of 59 genes associated with a life-threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medicallyactionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59-ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome-wide analysis, including chromosomal microarray and exome/genome sequencing.

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CNVs affecting cancer predisposing genes (CPGs) detected as incidental findings in routine germline diagnostic chromosomal microarray (CMA) testing

Cited by 9 publications

References 41 publications

Prevalence and properties of intragenic copy-number variation in Mendelian disease genes

Prevalence and properties of intragenic copy-number variation in Mendelian disease genes

Integrated Sequencing & Array Comparative Genomic Hybridization in Familial Parkinson’s Disease

Copy number alterations involving 59 ACMG‐recommended secondary findings genes

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