eP343: Long-read genome sequencing informs the molecular etiology of imprinting disorders

Dixon, Katherine; Shen, Yaoqing; Chin, Hui-Lin; Gazzaz, Nour; Huynh, Stephanie; Chan, Simon K.; Zhang, Cathy; Culibrk, Luka; O’Neill, Kieran; Mungall, Karen; Moore, Richard A.; Gibson, William T.; Chanoine, Jean-Pierre; Boerkoel, Cornelius F.; Jones, Steven J.M.

doi:10.1016/j.gim.2022.01.378

Cited by 1 publication

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“…Few studies tested the clinical application of LRS for the diagnosis of imprinting disorders, probably due to the still high costs of the technology. Long-read genome sequencing has been recently used to analyze two patients with imprinting disorders, identifying a loss of methylation at IC2 locus at 11p15 responsible for BWS in one case and maternal UPD at 15q11 causing PWS in the other case ( Dixon et al, 2022 ). The genome-wide approach also allowed researchers to investigate the additive contribution of possibly pathogenic variants in different genes to the clinical picture of patients.…”

Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%

Long read sequencing on its way to the routine diagnostics of genetic diseases

Olivucci,

Iovino,

Innella

et al. 2024

Front. Genet.

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The clinical application of technological progress in the identification of DNA alterations has always led to improvements of diagnostic yields in genetic medicine. At chromosome side, from cytogenetic techniques evaluating number and gross structural defects to genomic microarrays detecting cryptic copy number variants, and at molecular level, from Sanger method studying the nucleotide sequence of single genes to the high-throughput next-generation sequencing (NGS) technologies, resolution and sensitivity progressively increased expanding considerably the range of detectable DNA anomalies and alongside of Mendelian disorders with known genetic causes. However, particular genomic regions (i.e., repetitive and GC-rich sequences) are inefficiently analyzed by standard genetic tests, still relying on laborious, time-consuming and low-sensitive approaches (i.e., southern-blot for repeat expansion or long-PCR for genes with highly homologous pseudogenes), accounting for at least part of the patients with undiagnosed genetic disorders. Third generation sequencing, generating long reads with improved mappability, is more suitable for the detection of structural alterations and defects in hardly accessible genomic regions. Although recently implemented and not yet clinically available, long read sequencing (LRS) technologies have already shown their potential in genetic medicine research that might greatly impact on diagnostic yield and reporting times, through their translation to clinical settings. The main investigated LRS application concerns the identification of structural variants and repeat expansions, probably because techniques for their detection have not evolved as rapidly as those dedicated to single nucleotide variants (SNV) identification: gold standard analyses are karyotyping and microarrays for balanced and unbalanced chromosome rearrangements, respectively, and southern blot and repeat-primed PCR for the amplification and sizing of expanded alleles, impaired by limited resolution and sensitivity that have not been significantly improved by the advent of NGS. Nevertheless, more recently, with the increased accuracy provided by the latest product releases, LRS has been tested also for SNV detection, especially in genes with highly homologous pseudogenes and for haplotype reconstruction to assess the parental origin of alleles with de novo pathogenic variants. We provide a review of relevant recent scientific papers exploring LRS potential in the diagnosis of genetic diseases and its potential future applications in routine genetic testing.

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Section: Methylation Changes At Imprinted Genomic Regionsmentioning

confidence: 99%