2023 ACMG Annual Clinical Genetics Meeting Digital Edition: Poster Gallery-Diagnostic yield of copy number variants by exome sequencing versus chromosomal microarray

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This document presents a study comparing the detection of copy number variants (CNVs) using chromosomal microarray (CMA) and exome sequencing (ES) in over 8000 patients with congenital anomalies, developmental delay, or intellectual disability. The study aims to determine if ES is comparable to CMA in terms of CNV yield. <br /><br />The results show that the detection rate of CNVs by ES was 93.4%, slightly higher than the reported rate of 90.5% by CMA. Some CNVs detected by ES were not initially reported due to a lack of apparent phenotypic fit. However, the authors have updated their reporting methods to include more CNVs, even if the phenotype is not a clear fit, for consistency with CMA reporting.<br /><br />The study also suggests that ES has an advantage in detecting small CNVs below the threshold of CMA. In cases where CNVs were reported as positive on CMA but not detected on ES, the reasons included failure to detect mosaicism, CNVs close to the detection limit of ES, lack of probe coverage, and difficulty detecting CNVs in sex chromosomes.<br /><br />On the other hand, in cases where CMA was negative but CNVs were reported on ES, the reasons included size and probe coverage cutoffs on CMA, likely benign classification or carrier status for an autosomal recessive disease, and CNVs in CMA artifact regions due to homology. Most of the CNVs reported on ES but not CMA were in a single gene, with a smaller portion being multi-gene CNVs.<br /><br />Overall, the study demonstrates that ES is an excellent tool for detecting CNVs and can be comparable to CMA. The findings support the use of ES as a first- or second-tier test in patients with congenital anomalies, developmental delay, or intellectual disability.

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Presenting Author - Ganka V. Douglas, PhD; Co-Author - Jeanne M. Meck, PhD; Co-Author - Lindsay Havens Dyer, BS; Co-Author - Rhonda Brandon, MS; Co-Author - Lisa M. Dyer, PhD; Co-Author - Patricia Fernandez Ferri, PhD, FACMG; Co-Author - Mingjuan Liao, PhD; Co-Author - Shuxi Liu, PhD; Co-Author - Ludmila Matyakhina, PhD; Co-Author - Evica Rajcan-Separovic, CCMG, ACMG; Co-Author - Laura M. Sack, PhD; Co-Author - May Sanyoura, PhD; Co-Author - Wei Wang, PhD; Co-Author - Paul Kruszka, MD;

Meta Tag

array CGH

Chromosomal Abnormalities

Clinical Cytogenetics

Exome sequencing

Genetic Testing

Genome sequencing

Intellectual disability

Malformation

Microarray

Molecular Cytogenetics

Phenotype

Sequencing

Co-Author Jeanne M. Meck, PhD

Co-Author Lindsay Havens Dyer, BS

Co-Author Rhonda Brandon, MS

Co-Author Lisa M. Dyer, PhD

Co-Author Patricia Fernandez Ferri, PhD, FACMG

Co-Author Mingjuan Liao, PhD

Co-Author Shuxi Liu, PhD

Co-Author Ludmila Matyakhina, PhD

Co-Author Evica Rajcan-Separovic, CCMG, ACMG

Co-Author Laura M. Sack, PhD

Co-Author May Sanyoura, PhD

Co-Author Wei Wang, PhD

Co-Author Paul Kruszka, MD

Presenting Author Ganka V. Douglas, PhD

Keywords

copy number variants

chromosomal microarray

exome sequencing

CNV yield

detection rate

phenotypic fit

probe coverage

mosaicism

sex chromosomes

autosomal recessive disease