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Article ; Online: Small insertions and deletions (INDELs) in human genomes.

Mullaney, Julienne M / Mills, Ryan E / Pittard, W Stephen / Devine, Scott E

2010 Volume 19, Issue R2, Page(s) R131–6

Abstract: ... deletions (INDELs) in human genomes. Over the past decade, several million small INDELs have been discovered ... in human populations and personal genomes. The amount of genetic variation that is caused by these small ... Many of these INDELs map to functionally important sites within human genes, and thus, are likely to influence human ...

Abstract	In this review, we focus on progress that has been made with detecting small insertions and deletions (INDELs) in human genomes. Over the past decade, several million small INDELs have been discovered in human populations and personal genomes. The amount of genetic variation that is caused by these small INDELs is substantial. The number of INDELs in human genomes is second only to the number of single nucleotide polymorphisms (SNPs), and, in terms of base pairs of variation, INDELs cause similar levels of variation as SNPs. Many of these INDELs map to functionally important sites within human genes, and thus, are likely to influence human traits and diseases. Therefore, small INDEL variation will play a prominent role in personalized medicine.
MeSH term(s)	Genetic Variation/genetics ; Genome, Human/genetics ; Humans ; Mutagenesis, Insertional/genetics ; Polymorphism, Single Nucleotide/genetics ; Sequence Deletion/genetics
Language	English
Publishing date	2010-09-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddq400
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Article ; Online: Small polymorphisms are a source of ancestral bias in structural variant breakpoint placement.

Audano, Peter A / Beck, Christine R

Genome research

2024 Volume 34, Issue 1, Page(s) 7–19

Abstract: ... by the Human Genome Structural Variation Consortium (HGSVC). We identify 882 SV insertions and 180 SV deletions ... of the SVs called in a human genome and can impact variant interpretation and annotation. These limitations ... High-quality genome assemblies and sophisticated algorithms have increased sensitivity for a wide ...

Abstract	High-quality genome assemblies and sophisticated algorithms have increased sensitivity for a wide range of variant types, and breakpoint accuracy for structural variants (SVs, ≥50 bp) has improved to near base pair precision. Despite these advances, many SV breakpoint locations are subject to systematic bias affecting variant representation. To understand why SV breakpoints are inconsistent across samples, we reanalyzed 64 phased haplotypes constructed from long-read assemblies released by the Human Genome Structural Variation Consortium (HGSVC). We identify 882 SV insertions and 180 SV deletions with variable breakpoints not anchored in tandem repeats (TRs) or segmental duplications (SDs). SVs called from aligned sequencing reads increase breakpoint disagreements by 2×-16×. Sequence accuracy had a minimal impact on breakpoints, but we observe a strong effect of ancestry. We confirm that SNP and indel polymorphisms are enriched at shifted breakpoints and are also absent from variant callsets. Breakpoint homology increases the likelihood of imprecise SV calls and the distance they are shifted, and tandem duplications are the most heavily affected SVs. Because graph genome methods normalize SV calls across samples, we investigated graphs generated by two different methods and find the resulting breakpoints are subject to other technical biases affecting breakpoint accuracy. The breakpoint inconsistencies we characterize affect ∼5% of the SVs called in a human genome and can impact variant interpretation and annotation. These limitations underscore a need for algorithm development to improve SV databases, mitigate the impact of ancestry on breakpoints, and increase the value of callsets for investigating breakpoint features.
MeSH term(s)	Humans ; Sequence Analysis ; Algorithms ; Genome, Human ; Genomic Structural Variation ; Bias ; Sequence Analysis, DNA/methods ; High-Throughput Nucleotide Sequencing
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1284872-4
ISSN	1549-5469 ; 1088-9051 ; 1054-9803
ISSN (online)	1549-5469
ISSN	1088-9051 ; 1054-9803
DOI	10.1101/gr.278203.123
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Article: Small allelic variants are a source of ancestral bias in structural variant breakpoint placement.

Audano, Peter A / Beck, Christine R

bioRxiv : the preprint server for biology

2023

Abstract: ... breakpoints for 882 SV insertions and 180 SV deletions not anchored in tandem repeats (TRs) or ... callsets from the same sequencing data yielded 1,566 insertions and 986 deletions with inconsistent ... that polymorphic mismatches and small indels are enriched at shifted breakpoints and that these polymorphisms are ...

Abstract	High-quality genome assemblies and sophisticated algorithms have increased sensitivity for a wide range of variant types, and breakpoint accuracy for structural variants (SVs, ≥ 50 bp) has improved to near basepair precision. Despite these advances, many SVs in unique regions of the genome are subject to systematic bias that affects breakpoint location. This ambiguity leads to less accurate variant comparisons across samples, and it obscures true breakpoint features needed for mechanistic inferences. To understand why SVs are not consistently placed, we reanalyzed 64 phased haplotypes constructed from long-read assemblies released by the Human Genome Structural Variation Consortium (HGSVC). We identified variable breakpoints for 882 SV insertions and 180 SV deletions not anchored in tandem repeats (TRs) or segmental duplications (SDs). While this is unexpectedly high for genome assemblies in unique loci, we find read-based callsets from the same sequencing data yielded 1,566 insertions and 986 deletions with inconsistent breakpoints also not anchored in TRs or SDs. When we investigated causes for breakpoint inaccuracy, we found sequence and assembly errors had minimal impact, but we observed a strong effect of ancestry. We confirmed that polymorphic mismatches and small indels are enriched at shifted breakpoints and that these polymorphisms are generally lost when breakpoints shift. Long tracts of homology, such as SVs mediated by transposable elements, increase the likelihood of imprecise SV calls and the distance they are shifted. Tandem Duplication (TD) breakpoints are the most heavily affected SV class with 14% of TDs placed at different locations across haplotypes. While graph genome methods normalize SV calls across many samples, the resulting breakpoints are sometimes incorrect, highlighting a need to tune graph methods for breakpoint accuracy. The breakpoint inconsistencies we characterize collectively affect ~5% of the SVs called in a human genome and underscore a need for algorithm development to improve SV databases, mitigate the impact of ancestry on breakpoint placement, and increase the value of callsets for investigating mutational processes.
Language	English
Publishing date	2023-06-26
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.25.546295
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Article ; Online: TIVAN-indel: a computational framework for annotating and predicting non-coding regulatory small insertions and deletions.

Agarwal, Aman / Zhao, Fengdi / Jiang, Yuchao / Chen, Li

Bioinformatics (Oxford, England)

2023 Volume 39, Issue 2

Abstract: Motivation: Small insertion and deletion (sindel) of human genome has an important implication ... for human disease. One important mechanism for non-coding sindel (nc-sindel) to have an impact on human diseases and ... TIVAN-indel from the 'Whole Blood' tissue in GTEx and test the model using 15 immune cell types ...

Abstract	Motivation: Small insertion and deletion (sindel) of human genome has an important implication for human disease. One important mechanism for non-coding sindel (nc-sindel) to have an impact on human diseases and phenotypes is through the regulation of gene expression. Nevertheless, current sequencing experiments may lack statistical power and resolution to pinpoint the functional sindel due to lower minor allele frequency or small effect size. As an alternative strategy, a supervised machine learning method can identify the otherwise masked functional sindels by predicting their regulatory potential directly. However, computational methods for annotating and predicting the regulatory sindels, especially in the non-coding regions, are underdeveloped. Results: By leveraging labeled nc-sindels identified by cis-expression quantitative trait loci analyses across 44 tissues in Genotype-Tissue Expression (GTEx), and a compilation of both generic functional annotations and large-scale epigenomic profiles, we develop TIssue-specific Variant Annotation for Non-coding indel (TIVAN-indel), which is a supervised computational framework for predicting non-coding regulatory sindels. As a result, we demonstrate that TIVAN-indel achieves the best prediction performance in both with-tissue prediction and cross-tissue prediction. As an independent evaluation, we train TIVAN-indel from the 'Whole Blood' tissue in GTEx and test the model using 15 immune cell types from an independent study named Database of Immune Cell Expression. Lastly, we perform an enrichment analysis for both true and predicted sindels in key regulatory regions such as chromatin interactions, open chromatin regions and histone modification sites, and find biologically meaningful enrichment patterns. Availability and implementation: https://github.com/lichen-lab/TIVAN-indel. Supplementary information: Supplementary data are available at Bioinformatics online.
MeSH term(s)	Humans ; Quantitative Trait Loci ; Epigenomics ; Regulatory Sequences, Nucleic Acid ; Chromatin ; INDEL Mutation
Chemical Substances	Chromatin
Language	English
Publishing date	2023-01-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1422668-6
ISSN	1367-4811 ; 1367-4803
ISSN (online)	1367-4811
ISSN	1367-4803
DOI	10.1093/bioinformatics/btad060
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Article ; Online: Genomic profiling of NGS-based ctDNA from Chinese non-small cell lung cancer patients.

Xi, Yanfeng / Bai, Zhongyuan / Gao, Sihang / Guo, Jianghong / Zhang, Zhen / Zhang, Hongling / Qu, Li / Xu, Bing / Wang, Weiwei / Shan, Guangyu / Cui, Wei / Bai, Wenqi / Ji, Xiaoyong

Journal of cancer research and clinical oncology

2023 Volume 149, Issue 11, Page(s) 8573–8580

Abstract: ... and deletions (InDels). The most frequent genes were TP53 (32%), EGFR (31.97%), KRAS (6.46%), PIK3CA ... the concordance rate was 99.8% (418/419) for single-nucleotide variants (SNVs) and 96.7% (146/151) for insertions ... of the NGS-based ctDNA assay and to identify the genomic alteration profile of ctDNA in real-world Chinese ...

Abstract	Purpose: Cell-free circulating tumor DNA (ctDNA) in plasma enables rapid and repeat testing of actionable mutations. Next-generation sequencing (NGS) is an attractive platform for multiplex sequencing capabilities compared to traditional methods such as PCR. The purpose of this study is to evaluate the value of the NGS-based ctDNA assay and to identify the genomic alteration profile of ctDNA in real-world Chinese non-small cell lung (NSCLC) patients. Methods: In total, 294 Chinese patients with pathological diagnosis of Phase III-IV NSCLC were enrolled. 3-4 mL peripheral blood was collected and NGS-based analysis was carried out using a 20-gene panel. The analytical sensitivity and specificity of ctDNA NGS-based assay was validated using droplet digital PCR (ddPCR). Results: We have tested 570 sites from 286 samples using ddPCR, which included 108 positive sites and 462 negative sites from NGS results, and the concordance rate was 99.8% (418/419) for single-nucleotide variants (SNVs) and 96.7% (146/151) for insertions and deletions (InDels). The most frequent genes were TP53 (32%), EGFR (31.97%), KRAS (6.46%), PIK3CA (4.76%), and MET (4.08%). Exon 19 deletion (19del) was the most common alteration in EGFR and G12C was the most common alteration in KRAS. Furthermore, the detection rate of TP53 was higher in the male and patients with squamous cell carcinoma. We also found the prevalence of TP53 in L858R was higher than in 19del (61.29% vs. 40%; p = 0.1115). Conclusion: The results indicate that the results of NGS-based ctDNA assay are highly consistent with ddPCR. In Chinese NSCLC patients, TP53 mutation was more frequently associated with male and squamous cell carcinoma. The prevalence of concomitant mutations in L858R may be different from that in 19del.
MeSH term(s)	Humans ; Male ; Biomarkers, Tumor/genetics ; Carcinoma, Non-Small-Cell Lung/genetics ; Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Squamous Cell/genetics ; Circulating Tumor DNA/genetics ; East Asian People ; ErbB Receptors/genetics ; Genomics ; High-Throughput Nucleotide Sequencing/methods ; Lung Neoplasms/pathology ; Mutation ; Proto-Oncogene Proteins p21(ras)/genetics ; Female
Chemical Substances	Biomarkers, Tumor ; Circulating Tumor DNA ; ErbB Receptors (EC 2.7.10.1) ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
Language	English
Publishing date	2023-04-25
Publishing country	Germany
Document type	Journal Article
ZDB-ID	134792-5
ISSN	1432-1335 ; 0171-5216 ; 0084-5353 ; 0943-9382
ISSN (online)	1432-1335
ISSN	0171-5216 ; 0084-5353 ; 0943-9382
DOI	10.1007/s00432-023-04794-z
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Article ; Online: A rapid, multiplex digital PCR assay to detect gene variants and fusions in non-small cell lung cancer.

Leatham, Bryan / McNall, Katie / Subramanian, Hari K K / Jacky, Lucien / Alvarado, John / Yurk, Dominic / Wang, Mimi / Green, Donald C / Tsongalis, Gregory J / Rajagopal, Aditya / Schwartz, Jerrod J

Molecular oncology

2023 Volume 17, Issue 11, Page(s) 2221–2234

Abstract: ... assay capable of detecting 12 single-nucleotide and insertion/deletion (indel) variants in EGFR, KRAS ... Digital PCR (dPCR) is emerging as an ideal platform for the detection and tracking of genomic ... variants in cancer due to its high sensitivity and simple workflow. The growing number of clinically ...

Abstract	Digital PCR (dPCR) is emerging as an ideal platform for the detection and tracking of genomic variants in cancer due to its high sensitivity and simple workflow. The growing number of clinically actionable cancer biomarkers creates a need for fast, accessible methods that allow for dense information content and high accuracy. Here, we describe a proof-of-concept amplitude modulation-based multiplex dPCR assay capable of detecting 12 single-nucleotide and insertion/deletion (indel) variants in EGFR, KRAS, BRAF, and ERBB2, 14 gene fusions in ALK, RET, ROS1, and NTRK1, and MET exon 14 skipping present in non-small cell lung cancer (NSCLC). We also demonstrate the use of multi-spectral target-signal encoding to improve the specificity of variant detection by reducing background noise by up to an order of magnitude. The assay reported an overall 100% positive percent agreement (PPA) and 98.5% negative percent agreement (NPA) compared with a sequencing-based assay in a cohort of 62 human formalin-fixed paraffin-embedded (FFPE) samples. In addition, the dPCR assay rescued actionable information in 10 samples that failed to sequence, highlighting the utility of a multiplexed dPCR assay as a potential reflex solution for challenging NSCLC samples.
MeSH term(s)	Humans ; Carcinoma, Non-Small-Cell Lung/genetics ; Lung Neoplasms/genetics ; Lung Neoplasms/diagnosis ; Proto-Oncogene Proteins/genetics ; Receptor Protein-Tyrosine Kinases/genetics ; Polymerase Chain Reaction ; Mutation ; High-Throughput Nucleotide Sequencing
Chemical Substances	Proto-Oncogene Proteins ; Receptor Protein-Tyrosine Kinases (EC 2.7.10.1)
Language	English
Publishing date	2023-10-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2415106-3
ISSN	1878-0261 ; 1574-7891
ISSN (online)	1878-0261
ISSN	1574-7891
DOI	10.1002/1878-0261.13523
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Article ; Online: Targeted RNA sequencing for upfront analysis of actionable driver alterations in non-small cell lung cancer.

Claerhout, Sofie / Lehnert, Stefan / Vander Borght, Sara / Spans, Lien / Dooms, Christophe / Wauters, Els / Vansteenkiste, Johan / Weynand, Birgit / Deraedt, Karen / Bourgain, Claire / Vanden Bempt, Isabelle

Lung cancer (Amsterdam, Netherlands)

2022 Volume 166, Page(s) 242–249

Abstract: ... insertions/deletions. In this study, we evaluated the performance of tRNA-seq using Archer FusionPlex ... for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in formalin-fixed, paraffin ... followed by tRNA-seq.: Results: All 28 SNVs and indels in the validation set, and 34 out of 35 mutations ...

Abstract	Objectives: Targeted RNA-based Next-Generation Sequencing (tRNA-seq) is increasingly being used in molecular diagnostics for gene fusion detection in non-small cell lung cancer (NSCLC). However, few data support its clinical application for the detection of single nucleotide variants (SNVs) and small insertions/deletions. In this study, we evaluated the performance of tRNA-seq using Archer FusionPlex for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in formalin-fixed, paraffin-embedded NSCLC tissue. Materials and methods: A total of 126 NSCLC samples, including 20 validation samples and 106 diagnostic cases, were analyzed by targeted DNA-based Next-Generation Sequencing (tDNA-seq) followed by tRNA-seq. Results: All 28 SNVs and indels in the validation set, and 34 out of 35 mutations in the diagnostic set were identified by tRNA-seq. The only mutation undetected by tRNA-seq, ERBB2 p.(Ser310Tyr), was not included in the current Archer panel design. tRNA-seq revealed one additional BRAF p.(Val600Glu) mutation not found by tDNA-seq. SNVs and indels were correctly called by the vendor supplied software, except for ERBB2 duplication p.(Tyr772_A775dup) which was only detected by an additional in-house developed bio-informatics pipeline. Variant allelic frequency (VAF) values were generally higher at the expression level compared to the genomic level (range 6-96% for tRNA-seq versus 6-61% for tDNA-seq) and low VAF mutations in DNA (6-8% VAF) were all confirmed by tRNA-seq. Finally, tRNA-seq additionally identified a driver fusion or splice variant in 10 diagnostic NSCLC samples including one MET exon 14 skipping variant not detected by tDNA-seq. Conclusion: Our results demonstrate that tRNA-seq can be implemented in a diagnostic setting as an efficient strategy for simultaneous detection of actionable gene fusions, splice variants, SNVs and indels in NSCLC provided that adequate RNA-seq analysis tools are available, especially for the detection of indels. This approach allows upfront identification of currently recommended targetable molecular alterations in NSCLC samples.
MeSH term(s)	Carcinoma, Non-Small-Cell Lung/diagnosis ; Carcinoma, Non-Small-Cell Lung/genetics ; DNA ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Mutation ; Sequence Analysis, RNA/methods
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-03-01
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2022.02.013
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Article ; Online: Elucidation of de novo small insertion/deletion biology with parent-of-origin phasing.

Seiden, Allison H / Richter, Felix / Patel, Nihir / Rodriguez, Oscar L / Deikus, Gintaras / Shah, Hardik / Smith, Melissa / Roberts, Amy / King, Eileen C / Sebra, Robert P / Sharp, Andrew J / Gelb, Bruce D

Human mutation

2020 Volume 41, Issue 4, Page(s) 800–806

Abstract: The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage ... have been hypothesized but not well characterized in the human genome. We implemented two ... phasing compared to short-read sequencing (medians of 84% and 23%, respectively). We then wrote ...

Abstract	The mechanisms underlying de novo insertion/deletion (indel) genesis, such as polymerase slippage, have been hypothesized but not well characterized in the human genome. We implemented two methodological improvements, which were leveraged to dissect indel mutagenesis. We assigned de novo variants to parent-of-origin (i.e., phasing) with low-coverage long-read whole-genome sequencing, achieving better phasing compared to short-read sequencing (medians of 84% and 23%, respectively). We then wrote an application programming interface to classify indels into three subtypes according to sequence context. Across three cohorts with different phasing methods (N
MeSH term(s)	Computational Biology/methods ; Genome, Human ; Genomics/methods ; High-Throughput Nucleotide Sequencing ; Humans ; INDEL Mutation ; Polymorphism, Single Nucleotide ; Software
Language	English
Publishing date	2020-01-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1126646-6
ISSN	1098-1004 ; 1059-7794
ISSN (online)	1098-1004
ISSN	1059-7794
DOI	10.1002/humu.23971
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Article ; Online: SigProfilerMatrixGenerator: a tool for visualizing and exploring patterns of small mutational events.

Bergstrom, Erik N / Huang, Mi Ni / Mahto, Uma / Barnes, Mark / Stratton, Michael R / Rozen, Steven G / Alexandrov, Ludmil B

BMC genomics

2019 Volume 20, Issue 1, Page(s) 685

Abstract: ... substitutions, doublet base substitutions, and small insertions and deletions. While the tool provides ... to provide support for classifying doublet base substitutions and small insertions and deletions ... insertions, deletions, and doublet substitutions) can be used to provide a deeper understanding ...

Abstract	Background: Cancer genomes are peppered with somatic mutations imprinted by different mutational processes. The mutational pattern of a cancer genome can be used to identify and understand the etiology of the underlying mutational processes. A plethora of prior research has focused on examining mutational signatures and mutational patterns from single base substitutions and their immediate sequencing context. We recently demonstrated that further classification of small mutational events (including substitutions, insertions, deletions, and doublet substitutions) can be used to provide a deeper understanding of the mutational processes that have molded a cancer genome. However, there has been no standard tool that allows fast, accurate, and comprehensive classification for all types of small mutational events. Results: Here, we present SigProfilerMatrixGenerator, a computational tool designed for optimized exploration and visualization of mutational patterns for all types of small mutational events. SigProfilerMatrixGenerator is written in Python with an R wrapper package provided for users that prefer working in an R environment. SigProfilerMatrixGenerator produces fourteen distinct matrices by considering transcriptional strand bias of individual events and by incorporating distinct classifications for single base substitutions, doublet base substitutions, and small insertions and deletions. While the tool provides a comprehensive classification of mutations, SigProfilerMatrixGenerator is also faster and more memory efficient than existing tools that generate only a single matrix. Conclusions: SigProfilerMatrixGenerator provides a standardized method for classifying small mutational events that is both efficient and scalable to large datasets. In addition to extending the classification of single base substitutions, the tool is the first to provide support for classifying doublet base substitutions and small insertions and deletions. SigProfilerMatrixGenerator is freely available at https://github.com/AlexandrovLab/SigProfilerMatrixGenerator with an extensive documentation at https://osf.io/s93d5/wiki/home/ .
MeSH term(s)	Genomics/methods ; Humans ; INDEL Mutation ; Mutation ; Neoplasms/genetics ; Software
Language	English
Publishing date	2019-08-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2041499-7
ISSN	1471-2164 ; 1471-2164
ISSN (online)	1471-2164
ISSN	1471-2164
DOI	10.1186/s12864-019-6041-2
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Article ; Online: Candidate Genes in Testing Strategies for Linkage Analysis and Bioinformatic Sorting of Whole Genome Sequencing Data in Three Small Japanese Families with Idiopathic Superior Oblique Muscle Palsy.

Matsuo, Toshihiko / Chaomulige / Miyaji, Mary / Hosoya, Osamu / Saito, Akira / Nakazono, Kazuyuki

International journal of molecular sciences

2022 Volume 23, Issue 15

Abstract: ... genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were ... was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores ... SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels ...

Abstract	Idiopathic superior oblique muscle palsy is a major type of paralytic, non-comitant strabismus and presents vertical and cyclo-torsional deviation of one eye against the other eye, with a large vertical fusion range and abnormal head posture such as head tilt. Genetic background is considered to play a role in its development, as patients with idiopathic superior oblique muscle palsy have varying degrees of muscle hypoplasia and, rarely, the complete absence of the muscle, that is, aplasia. In this study, whole genome sequencing was performed, and single nucleotide variations and short insertions/deletions (SNVs/InDels) were annotated in two patients each in three small families (six patients in total) with idiopathic superior oblique muscle palsy, in addition to three normal individuals in one family. At first, linkage analysis was carried out in the three families and SNVs/InDels in chromosomal loci with negative LOD scores were excluded. Next, SNVs/InDels shared by the six patients, but not by the three normal individuals, were chosen. SNVs/InDels were further narrowed down by choosing low-frequency (<1%) or non-registered SNVs/InDels in four databases for the Japanese population, and then by choosing SNVs/InDels with functional influence, leading to one candidate gene, SSTR5-AS1 in chromosome 16. The six patients were heterozygous for 13-nucleotide deletion in SSTR5-AS1, except for one homozygous patient, while the three normal individuals were wild type. Targeted polymerase chain reaction (PCR) and direct sequencing of PCR products confirmed the 13-nucleotide deletion in SSTR5-AS1. In the face of newly-registered SSTR5-AS1 13-nucleotide deletion at a higher frequency in a latest released database for the Japanese population, the skipping of low-frequency and non-registration sorting still resulted in only 13 candidate genes including SSTR5-AS1 as common variants. The skipping of linkage analysis also led to the same set of 13 candidate genes. Different testing strategies that consisted of linkage analysis and simple unintentional bioinformatics could reach candidate genes in three small families with idiopathic superior oblique muscle palsy.
MeSH term(s)	Computational Biology ; Humans ; Japan ; Nucleotides ; Oculomotor Muscles ; Paralysis ; Whole Genome Sequencing
Chemical Substances	Nucleotides
Language	English
Publishing date	2022-08-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23158626
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