scholarly journals Long-read trio sequencing of individuals with unsolved intellectual disability

2020 ◽  
Author(s):  
Marc Pauper ◽  
Erdi Kucuk ◽  
Aaron M. Wenger ◽  
Shreyasee Chakraborty ◽  
Primo Baybayan ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Added Value ◽  
De Novo Mutation ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Sequence Coverage ◽  
Nucleotide Substitutions ◽  
Genome Variation ◽  
Long Read

AbstractLong-read sequencing (LRS) has the potential to comprehensively identify all medically relevant genome variation, including variation commonly missed by short-read sequencing (SRS) approaches. To determine this potential, we performed LRS around 15×–40× genome coverage using the Pacific Biosciences Sequel I System for five trios. The respective probands were diagnosed with intellectual disability (ID) whose etiology remained unresolved after SRS exomes and genomes. Systematic assessment of LRS coverage showed that ~35 Mb of the human reference genome was only accessible by LRS and not SRS. Genome-wide structural variant (SV) calling yielded on average 28,292 SV calls per individual, totaling 12.9 Mb of sequence. Trio-based analyses which allowed to study segregation, showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming that these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, ~100,000 were located in the ~35 Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known Mendelian disease genes. Our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.

scholarly journals A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

2021 ◽  
Author(s):  
Ying Zhang ◽  
Yanyan Nie ◽  
Yu Mu ◽  
Jie Zheng ◽  
Xiaowei Xu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mental Disorders ◽  
De Novo ◽  
Clinical Symptoms ◽  
Clinical Manifestations ◽  
De Novo Mutation ◽  
Loss Of Function ◽  
Bioinformatics Analyses ◽  
Whole Exome ◽  
De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

scholarly journals A De Novo Mutation in DYRK1A Causes Syndromic Intellectual Disability: A Chinese Case Report

2019 ◽  
Vol 10 ◽  
Author(s):  
Fengchang Qiao ◽  
Binbin Shao ◽  
Chen Wang ◽  
Yan Wang ◽  
Ran Zhou ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
De Novo ◽  
De Novo Mutation ◽  
Chinese Case

A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability

2019 ◽  
Vol 179 (6) ◽  
pp. 936-939 ◽  
Author(s):  
Ling Zhang ◽  
Ximing Xu ◽  
Kaiqiang Sun ◽  
Jingchuan Sun ◽  
Yuan Wang ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Spina Bifida ◽  
De Novo ◽  
De Novo Mutation ◽  
Craniofacial Malformation

scholarly journals Expectations and blind spots for structural variation detection from short-read alignment and long-read assembly

2020 ◽  
Author(s):  
Xuefang Zhao ◽  
Ryan L. Collins ◽  
Wan-Ping Lee ◽  
Alexandra M. Weber ◽  
Yukyung Jun ◽  
...  
Keyword(s):  
Single Molecule ◽  
Large Scale ◽  
Structural Variation ◽  
Human Genetics ◽  
Clinical Diagnostics ◽  
Added Value ◽  
Mendelian Disease ◽  
Segmental Duplications ◽  
Genomic Context ◽  
Long Read

AbstractVirtually all genome sequencing efforts in national biobanks, complex and Mendelian disease programs, and emerging clinical diagnostic approaches utilize short-reads (srWGS), which present constraints for genome-wide discovery of structural variants (SVs). Alternative long-read single molecule technologies (lrWGS) offer significant advantages for genome assembly and SV detection, while these technologies are currently cost prohibitive for large-scale disease studies and clinical diagnostics (∼5-12X higher cost than comparable coverage srWGS). Moreover, only dozens of such genomes are currently publicly accessible by comparison to millions of srWGS genomes that have been commissioned for international initiatives. Given this ubiquitous reliance on srWGS in human genetics and genomics, we sought to characterize and quantify the properties of SVs accessible to both srWGS and lrWGS to establish benchmarks and expectations in ongoing medical and population genetic studies, and to project the added value of SVs uniquely accessible to each technology. In analyses of three trios with matched srWGS and lrWGS from the Human Genome Structural Variation Consortium (HGSVC), srWGS captured ∼11,000 SVs per genome using reference-based algorithms, while haplotype-resolved assembly from lrWGS identified ∼25,000 SVs per genome. Detection power and precision for SV discovery varied dramatically by genomic context and variant class: 9.7% of the current GRCh38 reference is defined by segmental duplications (SD) and simple repeats (SR), yet 91.4% of deletions that were specifically discovered by lrWGS localized to these regions. Across the remaining 90.3% of the human reference, we observed extremely high concordance (93.8%) for deletions discovered by srWGS and lrWGS after error correction using the raw lrWGS reads. Conversely, lrWGS was superior for detection of insertions across all genomic contexts. Given that the non-SD/SR sequences span 90.3% of the GRCh38 reference, and encompass 95.9% of coding exons in currently annotated disease associated genes, improved sensitivity from lrWGS to discover novel and interpretable pathogenic deletions not already accessible to srWGS is likely to be incremental. However, these analyses highlight the added value of assembly-based lrWGS to create new catalogues of functional insertions and transposable elements, as well as disease associated repeat expansions in genomic regions previously recalcitrant to routine assessment.

scholarly journals A whole genome atlas of 81 Psilocybe genomes as a resource for psilocybin production.

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 961
Author(s):  
Kevin McKernan ◽  
Liam Kane ◽  
Yvonne Helbert ◽  
Lei Zhang ◽  
Nathan Houde ◽  
...  
Keyword(s):  
Gene Cluster ◽  
Single Molecule ◽  
Reference Genome ◽  
De Novo ◽  
Genomic Diversity ◽  
Sequence Coverage ◽  
Single Molecule Sequencing ◽  
Contiguous Gene ◽  
Long Read ◽  
Interesting Variation

The Psilocybe genus is well known for the synthesis of valuable psychoactive compounds such as Psilocybin, Psilocin, Baeocystin and Aeruginascin. The ubiquity of Psilocybin synthesis in Psilocybe has been attributed to a horizontal gene transfer mechanism of a ~20Kb gene cluster. A recently published highly contiguous reference genome derived from long read single molecule sequencing has underscored interesting variation in this Psilocybin synthesis gene cluster. This reference genome has also enabled the shotgun sequencing of spores from many Psilocybe strains to better catalog the genomic diversity in the Psilocybin synthesis pathway. Here we present the de novo assembly of 81 Psilocybe genomes compared to the P.envy reference genome. Surprisingly, the genomes of Psilocybe galindoi, Psilocybe tampanensis and Psilocybe azurescens lack sequence coverage over the previously described Psilocybin synthesis pathway but do demonstrate amino acid sequence homology to a less contiguous gene cluster and may illuminate the previously proposed evolution of psilocybin synthesis.

scholarly journals Human and mouse essentiality screens as a resource for disease gene discovery

2019 ◽  
Author(s):  
Pilar Cacheiro ◽  
Violeta Muñoz-Fuentes ◽  
Stephen A. Murray ◽  
Mary E. Dickinson ◽  
Maja Bucan ◽  
...  
Keyword(s):  
Developmental Disorders ◽  
Disease Gene ◽  
De Novo ◽  
Genetic Diseases ◽  
Gene Discovery ◽  
Tissue Expression ◽  
Human Cell Line ◽  
Disease Genes ◽  
Mendelian Disease ◽  
Disease Gene Discovery

ABSTRACTAlthough genomic sequencing has been transformative in the study of rare genetic diseases, identifying causal variants remains a considerable challenge that can be addressed in part by new gene-specific knowledge. Here, we integrate measures of how essential a gene is to supporting life, as inferred from the comprehensive viability and phenotyping screens performed on knockout mice by the International Mouse Phenotyping Consortium and from human cell line essentiality screens. We propose a novel, cross-species gene classification across the Full Spectrum of Intolerance to Loss-of-function (FUSIL) and demonstrate that genes in five mutually exclusive FUSIL categories have differing characteristics in the biological processes they regulate, tissue expression levels and human mutation rates. Most notably, Mendelian disease genes, particularly those associated with developmental disorders, are highly overrepresented in the developmental lethal category, representing genes not essential for cell survival but required for organism development. Exploiting this finding, we have screened developmental disorder cases from three independent disease sequencing consortia and identified potentially pathogenic, de novo variants shared in different patients for several developmental lethal genes that have not previously been associated with rare disease. We therefore propose FUSIL as an efficient resource for disease gene discovery.

scholarly journals Mapping Autosomal Recessive Intellectual Disability: Combined Microarray and Exome Sequencing Identifies 26 Novel Candidate Genes in 192 Consanguineous Families

2016 ◽  
Author(s):  
Ricardo Harripaul ◽  
Nasim Vasli ◽  
Anna Mikhailov ◽  
Muhammad Arshad Rafiq ◽  
Kirti Mittal ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Exome Sequencing ◽  
Autosomal Recessive ◽  
De Novo ◽  
Clinical Diagnostics ◽  
High Yield ◽  
Disease Genes ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Whole Exome

Approximately 1% of the global population is affected by intellectual disability (ID), and the majority receive no molecular diagnosis. Previous studies have indicated high levels of genetic heterogeneity, with estimates of more than 2500 autosomal ID genes, the majority of which are autosomal recessive (AR). Here, we combined microarray genotyping, homozygosity-by-descent (HBD) mapping, copy number variation (CNV) analysis, and whole exome sequencing (WES) to identify disease genes/mutations in 192 multiplex Pakistani and Iranian consanguineous families with non-syndromic ID. We identified definite or candidate mutations (or CNVs) in 51% of families in 72 different genes, including 26 not previously reported for ARID. The new ARID genes include nine with loss-of-function mutations(ABI2, MAPK8, MPDZ, PIDD1, SLAIN1, TBC1D23, TRAPPC6B, UBA7,andUSP44),and missense mutations include the first reports of variants inBDNForTET1associated with ID. The genes identified also showed overlap withde novogene sets for other neuropsychiatric disorders. Transcriptional studies showed prominent expression in the prenatal brain. The high yield of AR mutations for ID indicated that this approach has excellent clinical potential and should inform clinical diagnostics, including clinical whole exome and genome sequencing, for populations in which consanguinity is common. As with other AR disorders, the relevance will also apply to outbred populations.

A de novo mutation in FMR1 in a patient with intellectual disability

2020 ◽  
Vol 63 (3) ◽  
pp. 103763 ◽  
Author(s):  
Sateesh Maddirevula ◽  
Hessa S. Alsaif ◽  
Niema Ibrahim ◽  
Fowzan S. Alkuraya
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
De Novo Mutation

scholarly journals Draft genome assemblies using sequencing reads from Oxford Nanopore Technology and Illumina platforms for four species of North American Fundulus killifish

GigaScience ◽  
2020 ◽  
Vol 9 (6) ◽  
Author(s):  
Lisa K Johnson ◽  
Ruta Sahasrabudhe ◽  
James Anthony Gill ◽  
Jennifer L Roach ◽  
Lutz Froenicke ◽  
...  
Keyword(s):  
North American ◽  
De Novo ◽  
Draft Genome ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Sequence Coverage ◽  
Short Read ◽  
Oxford Nanopore ◽  
Long Read ◽  
Genome Assemblies

Abstract Background Whole-genome sequencing data from wild-caught individuals of closely related North American killifish species (Fundulus xenicus, Fundulus catenatus, Fundulus nottii, and Fundulus olivaceus) were obtained using long-read Oxford Nanopore Technology (ONT) PromethION and short-read Illumina platforms. Findings Draft de novo reference genome assemblies were generated using a combination of long and short sequencing reads. For each species, the PromethION platform was used to generate 30–45× sequence coverage, and the Illumina platform was used to generate 50–160× sequence coverage. Illumina-only assemblies were fragmented with high numbers of contigs, while ONT-only assemblies were error prone with low BUSCO scores. The highest N50 values, ranging from 0.4 to 2.7 Mb, were from assemblies generated using a combination of short- and long-read data. BUSCO scores were consistently >90% complete using the Eukaryota database. Conclusions High-quality genomes can be obtained from a combination of using short-read Illumina data to polish assemblies generated with long-read ONT data. Draft assemblies and raw sequencing data are available for public use. We encourage use and reuse of these data for assembly benchmarking and other analyses.

scholarly journals Neurodevelopmental disease genes implicated by de novo mutation and CNV morbidity

2017 ◽  
Author(s):  
Bradley P. Coe ◽  
Holly A.F. Stessman ◽  
Arvis Sulovari ◽  
Madeleine Geisheker ◽  
Fereydoun Hormozdiari ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Gene Dosage ◽  
De Novo Mutation ◽  
Disease Genes ◽  
Missense Mutations ◽  
Genomic Disorder ◽  
Network Analyses ◽  
Neurodevelopmental Disease ◽  
Deletion Syndromes

ABSTRACTWe combined de novo mutation (DNM) data from 10,927 cases of developmental delay and autism to identify 301 candidate neurodevelopmental disease genes showing an excess of missense and/or likely gene-disruptive (LGD) mutations. 164 genes were predicted by two different DNM models, including 116 genes with an excess of LGD mutations. Among the 301 genes, 76% show DNM in both autism and intellectual disability/developmental delay cohorts where they occur in 10.3% and 28.4% of the cases, respectively. Intersecting these results with copy number variation (CNV) morbidity data identifies a significant enrichment for the intersection of our gene set and genomic disorder regions (36/301, LR+ 2.53, p=0.0005). This analysis confirms many recurrent LGD genes and CNV deletion syndromes (e.g., KANSL1, PAFAH1B1, RA1, etc.), consistent with a model of haploinsufficiency. We also identify genes with an excess of missense DNMs overlapping deletion syndromes (e.g., KIF1A and the 2q37 deletion) as well as duplication syndromes, such as recurrent MAPK3 missense mutations within the chromosome 16p11.2 duplication, recurrent CHD4 missense DNMs in the 12p13 duplication region, and recurrent WDFY4 missense DNMs in the 10q11.23 duplication region. Finally, we also identify pathogenic CNVs overlapping more than one recurrently mutated gene (e.g., Sotos and Kleefstra syndromes) raising the possibility that multiple gene-dosage imbalances may contribute to phenotypic complexity of these disorders. Network analyses of genes showing an excess of DNMs confirm previous well-known enrichments but also highlight new functional networks, including cell-specific enrichments in the D1+ and D2+ spiny neurons of the striatum for both recurrently mutated genes and genes where missense mutations cluster.

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