Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders

Hiatt, Susan M.; Lawlor, James M.J.; Handley, Lori H.; Ramaker, Ryne C.; Rogers, Brianne B.; Partridge, Chris; Boston, Lori Beth; Williams, Melissa E.; Plott, Christopher; Jenkins, Jerry; Gray, David E.; Holt, James; Bowling, Kevin M.; Bebin, Martina; Grimwood, Jane; Schmutz, Jeremy; Cooper, Gregory M.

doi:10.1016/s1096-7192(21)00504-7

Cited by 9 publications

(6 citation statements)

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“…In contrast to GATK small variant calls, where recall rates against truth sets are known, there are not recall rates available for this employed combination of tools, though we note that there is a high false negative rate for all CNV callers from short read PCRpositive genome data; thus, the goal in CNV analysis was to have high confidence in those variants that were identifiable across all four callers at the expense of missing some true positives that may not pass these strict criteria. Better detection of expansions such as C9ORF72 or heretofore unidentified similar events and/or better large indel detection will be aided by emerging use of long read sequencing which can help identify events that would be missed otherwise [66].…”

Section: Genetic Screening For Disease Causing Variantsmentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

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Section: Genetic Screening For Disease Causing Variantsmentioning

confidence: 99%

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

et al. 2022

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“…Head-to-head PCR primers in the ectopic site were used to amplify the circles by iPCR (Fig. 3A), and the products were analyzed by PacBio long-read high-fidelity circular consensus sequencing (64).…”

Section: Single-molecule Analysis Of (Pu) 78 Dsbsmentioning

confidence: 99%

Stable G-quadruplex DNA structures promote replication-dependent genome instability

Rider

Gadgil

Hitch

et al. 2022

Journal of Biological Chemistry

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“…More recently, Hiatt et al used PacBio sequencing to identify pathogenic structural variation including complex rearrangements. In one of the probands, they identified a likely pathogenic de novo L1‐mediated insertion in CDKL5 (MIM# 300203) which was cryptic to short read sequencing (Hiatt et al, 2021). In another proband, they identified multiple de novo SVs including two insertional translocations in a chromothriptic event involving three chromosomes.…”

Section: Introductionmentioning

confidence: 99%

Long‐read sequencing for molecular diagnostics in constitutional genetic disorders

et al. 2022

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Long-read sequencing (LRS) has been around for more than a decade, but widespread adoption of the technology has been slow due to the perceived high error rates and high sequencing cost. This is changing due to the recent advancements to produce highly accurate sequences and the reducing costs. LRS Chromosomal microarrays (SNP arrays and array CompetitiveGenomic Hybridization [aCGH]) have been considered the gold standard to detect submicroscopic deletions and duplications greater than 50 kb in length for over a decade. Currently, CMA is a first-tier diagnostic test for many congenital disorders, including developmental delay, autism, and multiple congenital anomalies (D. T. Miller et al., 2010). Targeted arrays, often focusing on exonic regions, are also companions for panel-based or targeted gene testing. While

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Long-read genome sequencing for the molecular diagnosis of neurodevelopmental disorders

Cited by 9 publications

References 0 publications

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

A neurodegenerative disease landscape of rare mutations in Colombia due to founder effects

Stable G-quadruplex DNA structures promote replication-dependent genome instability

Long‐read sequencing for molecular diagnostics in constitutional genetic disorders

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