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2023 ACMG Annual Clinical Genetics Meeting Digital ...
Application of Long Read Whole Genome Sequenci ...
Application of Long Read Whole Genome Sequencing to elucidate the molecular etiology of a patient with diagnostic odyssey
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Pdf Summary
This case report highlights the importance of long-read whole genome sequencing (LRS) in characterizing a complex chromosomal rearrangement (CCR) and providing a molecular diagnosis for patients with challenging genetic conditions.<br /><br />The patient in this case is an 8-year-old boy with a range of clinical features including developmental delay, speech and language delays, hypotonia, obesity, and facial abnormalities. Standard genetic tests, including G-banding, microarray, and whole exome sequencing, had been performed but did not provide a definitive molecular etiology for the patient's symptoms.<br /><br />The researchers utilized LRS technologies (PacBio and ONT) in combination with complementary genetic tests to detect and characterize the structure of the de novo CCR in this patient. The LRS approach allowed for better resolution and mapping of the complex translocation involving chromosomes 2, 3, 8, and 21 at the nucleotide level.<br /><br />Discrepancies in the size of a heterozygous deletion at 2p16.1 were identified among the different genetic tests and were attributed to differences in probe coverage. Breakpoint junction PCR and Sanger sequencing are being used to validate the CCR breakpoints identified by LRS.<br /><br />Overall, this case study demonstrates the power of combining comprehensive cytogenomic and molecular techniques with long-molecule sequencing in characterizing complex chromosomal abnormalities and providing a molecular diagnosis for challenging cases. LRS technologies have the potential to significantly advance medical genetics and provide answers for patients with unresolved genetic conditions.<br /><br />The authors acknowledge the importance of further validating LRS findings and emphasize the goal of establishing LRS as a well-validated tool for resolving diagnostic puzzles in the future.<br /><br />References:<br />1. Miller, D. et al. (2021). Targeted long-read sequencing identified missing disease-causing variation. The American Journal of Human Genetics 108: 1436-1449.<br />2. Eisfeldt, J. et al. (2019). Comprehensive structural variation genome map of individuals carrying complex chromosomal rearrangements. PLOS Genetics 15(2): e1007858.<br />3. Li, H. (2018). Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics, 34:3094-3100.<br />4. Jiang, T. et al. (2020) Long-read-based human genomic structural variation detection with cuteSV. Genome Biol 21, 189.
Asset Subtitle
Presenting Author - Hieu T. Nguyen, PhD; Co-Author - Leah Frater-Rubsam, PhD; Co-Author - April Hall; Co-Author - Vanessa Horner, PhD, FACMG; Co-Author - Stephen Meyn, MD, PhD;
Meta Tag
Bioinformatics
Chromosomal Abnormalities
Companion Diagnostics
Congenital Anomaly
Genome sequencing
Genotype-Phenotype Correlations
Identification of Disease Genes
Sequencing
Co-Author
Leah Frater-Rubsam, PhD
Co-Author
April Hall
Co-Author
Vanessa Horner, PhD, FACMG
Co-Author
Stephen Meyn, MD, PhD
Presenting Author
Hieu T. Nguyen, PhD
Keywords
long-read whole genome sequencing
complex chromosomal rearrangement
molecular diagnosis
genetic conditions
developmental delay
speech and language delays
hypotonia
obesity
facial abnormalities
LRS technologies
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