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, E. Christopher; Boston, Lori Beth; Williams, Melissa E.; Plott, Christopher; Jenkins, Jerry; Gray, David E.; Holt, James; Bowling, Kevin M.; Bebin, E. Martina; Grimwood, Jane; Schmutz, Jeremy; Cooper, Gregory M.

doi:10.1016/j.xhgg.2021.100023

Cited by 31 publications

(33 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another explanation may be the technical limitations of currently available diagnostic methods. It has been shown, for example, that the application of long-read sequencing in NGS-based methods may clarify the genetic background in many unresolved cases ( Fujimoto et al, 2021 ; Hiatt et al, 2021 ; Miller et al, 2021 ; Rastegar and Yasui, 2021 ). Considering the above, the next steps that we should consider to implement for diagnosis of our unsolved cases include whole-genome sequencing, RNA-seq, whole-genome bisulfite sequencing, or long-read ES.…”

Section: Discussionmentioning

confidence: 99%

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects

Bukowska‐Olech

Sowińska‐Seidler

Larysz

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

Background: Craniosynostosis (CS) represents a highly heterogeneous genetic condition whose genetic background has not been yet revealed. The abnormality occurs either in isolated form or syndromic, as an element of hundreds of different inborn syndromes. Consequently, CS may often represent a challenging diagnostic issue.Methods: We investigated a three-tiered approach (karyotyping, Sanger sequencing, followed by custom gene panel/chromosomal microarray analysis, and exome sequencing), coupled with prioritization of variants based on dysmorphological assessment and description in terms of human phenotype ontology. In addition, we have also performed a statistical analysis of the obtained clinical data using the nonparametric test χ2.Results: We achieved a 43% diagnostic success rate and have demonstrated the complexity of mutations’ type harbored by the patients, which were either chromosomal aberrations, copy number variations, or point mutations. The majority of pathogenic variants were found in the well-known CS genes, however, variants found in genes associated with chromatinopathies or RASopathies are of particular interest.Conclusion: We have critically summarized and then optimised a cost-effective diagnostic algorithm, which may be helpful in a daily diagnostic routine and future clinical research of various CS types. Moreover, we have pinpointed the possible underestimated co-occurrence of CS and intellectual disability, suggesting it may be overlooked when intellectual disability constitutes a primary clinical complaint. On the other hand, in any case of already detected syndromic CS and intellectual disability, the possible occurrence of clinical features suggestive for chromatinopathies or RASopathies should also be considered.

show abstract

Section: Discussionmentioning

confidence: 99%

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects

Bukowska‐Olech

Sowińska‐Seidler

Larysz

et al. 2022

Front. Mol. Biosci.

View full text Add to dashboard Cite

show abstract

“…For example, LRS was able to fully reconstruct chromothripsis, a chaotic and complex genomic rearrangement, in a patient with Langer–Giedion syndrome (MIM# 150230) and Cornelia de Lange syndrome (MIM# 614701) [ 177 ]. However, some studies have successfully implicated genome-wide long-read sequencing in the discovery of complex SVs in Mendelian neurological disorders [ 178 , 179 , 180 ], including transposon-mediated events and complex SVs.…”

Section: Novel Dna Sequencing and Mapping Technologiesmentioning

confidence: 99%

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Kadlubowska

Schrauwen

2022

Genes

View full text Add to dashboard Cite

During the last decade, genetic testing has emerged as an important etiological diagnostic tool for Mendelian diseases, including pediatric neurological conditions. A genetic diagnosis has a considerable impact on disease management and treatment; however, many cases remain undiagnosed after applying standard diagnostic sequencing techniques. This review discusses various methods to improve the molecular diagnostic rates in these genomic cold cases. We discuss extended analysis methods to consider, non-Mendelian inheritance models, mosaicism, dual/multiple diagnoses, periodic re-analysis, artificial intelligence tools, and deep phenotyping, in addition to integrating various omics methods to improve variant prioritization. Last, novel genomic technologies, including long-read sequencing, artificial long-read sequencing, and optical genome mapping are discussed. In conclusion, a more comprehensive molecular analysis and a timely re-analysis of unsolved cases are imperative to improve diagnostic rates. In addition, our current understanding of the human genome is still limited due to restrictions in technologies. Novel technologies are now available that improve upon some of these limitations and can capture all human genomic variation more accurately. Last, we recommend a more routine implementation of high molecular weight DNA extraction methods that is coherent with the ability to use and/or optimally benefit from these novel genomic methods.

show abstract

“…In two patients, de novo translocations of chromosome 4 and 9, t (4;9) were identified to cause a disruption of the AF9 gene, resulting in neurodevelopmental delay with intellectual disability, growth delay, seizures and ataxia ( Pramparo et al, 2005 ; Striano et al, 2005 ). Long-read sequencing in a patient with intellectual disability and facial dysmorphism rendered AF9 heterozygous LoF as likely causative gene ( Hiatt et al, 2021 ).…”

Section: Super Elongation Complexmentioning

confidence: 99%

Transcription Pause and Escape in Neurodevelopmental Disorders

2022

View full text Add to dashboard Cite

Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

show abstract

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

Cited by 31 publications

References 61 publications

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects

Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects

Methods to Improve Molecular Diagnosis in Genomic Cold Cases in Pediatric Neurology

Transcription Pause and Escape in Neurodevelopmental Disorders

Contact Info

Product

Resources

About