Precision medicine validation: identifying the MYBPC3 A31P variant with whole-genome sequencing in two Maine Coon cats with hypertrophic cardiomyopathy

2018 ◽  
Vol 21 (12) ◽  
pp. 1086-1093 ◽  
Author(s):  
Eric S Ontiveros ◽  
Yu Ueda ◽  
Samantha P Harris ◽  
Joshua A Stern ◽  
Keyword(s):  
Heart Disease ◽  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Allele Frequency ◽  
Genome Sequencing ◽  
Disease Status ◽  
Whole Genome ◽  
Proof Of Concept ◽  
Separate Cohort

Objectives The objective of this study was to perform a proof-of-concept experiment that validates a precision medicine approach to identify variants associated with hypertrophic cardiomyopathy (HCM). We hypothesized that whole-genome sequencing would identify variant(s) associated with HCM in two affected Maine Coon/Maine Coon cross cats when compared with 79 controls of various breeds. Methods Two affected and two control Maine Coon/Maine Coon cross cats had whole-genome sequencing performed at approximately × 30 coverage. Variants were called in these four cats and 77 cats of various breeds as part of the 99 Lives Cat Genome Sequencing Initiative ( http://felinegenetics.missouri.edu/99lives ) using Platypus v0.7.9.1, annotated with dbSNP ID, and variants’ effect predicted by SnpEff. Strict filtering criteria (alternate allele frequency >49%) were applied to identify homozygous-alternate or heterozygous variants in the two HCM-affected samples when compared with 79 controls of various breeds. Results A total of four variants were identified in the two Maine Coon/Maine Coon cross cats with HCM when compared with 79 controls after strict filtering. Three of the variants identified in genes MFSD12, BTN1A1 and SLITRK5 did not segregate with disease in a separate cohort of seven HCM-affected and five control Maine Coon/Maine Coon cross cats. The remaining variant MYBPC3 segregated with disease status. Furthermore, this gene was previously associated with heart disease and encodes for a protein with sarcomeric function. Conclusions and relevance This proof-of-concept experiment identified the previously reported MYBPC3 A31P Maine Coon variant in two HCM-affected cases. This result validates and highlights the power of whole-genome sequencing for feline precision medicine.

scholarly journals Rapid whole genome sequencing impacts care and resource utilization in infants with congenital heart disease

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Nathaly M. Sweeney ◽  
Shareef A. Nahas ◽  
Sh. Chowdhury ◽  
Sergey Batalov ◽  
Michelle Clark ◽  
...  
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Disease ◽  
Congenital Heart ◽  
Cost Of Care ◽  
Morbidity And Mortality ◽  
Whole Genome ◽  
Microarray Gene

AbstractCongenital heart disease (CHD) is the most common congenital anomaly and a major cause of infant morbidity and mortality. While morbidity and mortality are highest in infants with underlying genetic conditions, molecular diagnoses are ascertained in only ~20% of cases using widely adopted genetic tests. Furthermore, cost of care for children and adults with CHD has increased dramatically. Rapid whole genome sequencing (rWGS) of newborns in intensive care units with suspected genetic diseases has been associated with increased rate of diagnosis and a net reduction in cost of care. In this study, we explored whether the clinical utility of rWGS extends to critically ill infants with structural CHD through a retrospective review of rWGS study data obtained from inpatient infants < 1 year with structural CHD at a regional children’s hospital. rWGS diagnosed genetic disease in 46% of the enrolled infants. Moreover, genetic disease was identified five times more frequently with rWGS than microarray ± gene panel testing in 21 of these infants (rWGS diagnosed 43% versus 10% with microarray ± gene panels, p = 0.02). Molecular diagnoses ranged from syndromes affecting multiple organ systems to disorders limited to the cardiovascular system. The average daily hospital spending was lower in the time period post blood collection for rWGS compared to prior (p = 0.003) and further decreased after rWGS results (p = 0.000). The cost was not prohibitive to rWGS implementation in the care of this cohort of infants. rWGS provided timely actionable information that impacted care and there was evidence of decreased hospital spending around rWGS implementation.

scholarly journals Novel BMD loci identified by whole genome sequencing and CRISPR editing in zebrafish: The NHLBI Trans-Omics for Precision Medicine (TOPMED) study

Bone Reports ◽  
2021 ◽  
Vol 14 ◽  
pp. 100765
Author(s):  
Yi-Hsiang Hsu ◽  
Joyce W. Tang ◽  
Hanfei Xu ◽  
Cecily Choy ◽  
May Montasser ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome

Abstract 343: Bayesian Selection of Modifier Genes in Hypertrophic Cardiomyopathy Through Whole Genome Sequencing

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Matthew Wheeler ◽  
Daryl Waggott ◽  
Megan Grove ◽  
Frederick Dewey ◽  
Cuiping Pan ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
A Priori ◽  
Copy Number Variants ◽  
Whole Genome Sequence ◽  
Monogenic Disease ◽  
Whole Genome ◽  
Genetic Modifiers ◽  
Structural Variants

Background: Technological advances have greatly reduced the cost of whole genome sequencing. For single individuals clinical application is apparent, while exome sequencing in tens of thousands of people has allowed a more global view of genetic variation that can inform interpretation of specific variants in individuals. We hypothesized that genome sequencing of patients with monogenic cardiomyopathy would facilitate discovery of genetic modifiers of phenotype. Methods and Results: We identified 48 individuals diagnosed with cardiomyopathy and with putative mutations in MYH7, the gene encoding beta myosin heavy chain. We carried out whole genome sequencing and applied a newly developed analytical pipeline optimized for discovery of genes modifying severity of clinical presentation and outcomes. Using a combination of external priors and rare variant burden tests we scored genes as potential modifiers. There were 96 genes that reached a modifier score of 6 out of 12 or better (9=2, 8=8, 7=17, 6=69). We identified NCKAP1, a gene that regulates actin filament dynamics, and CAMSAP1, a calmodulin regulate gene that regulates microtubule dynamics, as top scoring modifiers of hypertrophic cardiomyopathy phenotypes (score=9) while LDB2, RYR2, FBN1 and ATP1A2 had modifier scores of 8. Of the top scoring genes, 21 out of 96 were identified as candidates a priori. Our candidate prioritization scheme identified the previously described modifiers of cardiomyopathy phenotype, FHOD3 and MYBPC3, as top scoring genes. We identified structural variants in 21 clinically sequenced cardiomyopathy associated genes, 13 of which were at less than 10% frequency. Copy number variants in ILK and CSRP3 were nominally associated with ejection fraction (p=0.03), while 8 genes showed copy gains (GLA, FKTN, SGCD, TTN, SOS1, ANKRD1, VCL and NEBL). Structural variants were found in CSRP3, MYL3 and TNNC1, all of which have been implicated as causative for HCM. Conclusion: Evaluation of the whole genome sequence, even in the case of putatively monogenic disease, leads to important diagnostic and scientific insights not revealed by panel-based sequencing.

scholarly journals Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging

2020 ◽  
Vol 117 (6) ◽  
pp. 3053-3062 ◽  
Author(s):  
Ying-Chen Claire Hou ◽  
Hung-Chun Yu ◽  
Rick Martin ◽  
Elizabeth T. Cirulli ◽  
Natalie M. Schenker-Ahmed ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Clinical Laboratory ◽  
Descriptive Analysis ◽  
Disease Diagnosis ◽  
Whole Genome ◽  
Advanced Imaging ◽  
Family Medical History ◽  
Deep Phenotyping

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.

scholarly journals Precision Medicine in Cats: Novel Niemann-Pick Type C1 Diagnosed by Whole-Genome Sequencing

2017 ◽  
Vol 31 (2) ◽  
pp. 539-544 ◽  
Author(s):  
D.A. Mauler ◽  
B. Gandolfi ◽  
C.R. Reinero ◽  
D.P. O'Brien ◽  
J.L. Spooner ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Niemann Pick

scholarly journals Assessing reproducibility of inherited variants detected with short-read whole genome sequencing

2022 ◽  
Vol 23 (1) ◽  
Author(s):  
Bohu Pan ◽  
Luyao Ren ◽  
Vitor Onuchic ◽  
Meijian Guan ◽  
Rebecca Kusko ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Precision Medicine ◽  
Genome Sequencing ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
Short Read ◽  
Sequencing Platforms ◽  
The Impact ◽  
Two Populations

Abstract Background Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. Results To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. Conclusions Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.

scholarly journals Resistance-Conferring Mutations on Whole-Genome Sequencing of Fluoroquinolone-resistant and -Susceptible Mycobacterium tuberculosis Isolates: A Proposed Threshold for Identifying Resistance

2020 ◽  
Author(s):  
Fernanda Maruri ◽  
Yan Guo ◽  
Amondrea Blackman ◽  
Yuri F van der Heijden ◽  
Peter F Rebeiro ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Whole Genome Sequencing ◽  
Allele Frequency ◽  
Genome Sequencing ◽  
Dna Gyrase ◽  
Variant Allele ◽  
Whole Genome ◽  
Variant Allele Frequency ◽  
Predominant Variant ◽  
Frequency Threshold

Abstract Background Fluoroquinolone resistance in Mycobacterium tuberculosis (Mtb) is conferred by DNA gyrase mutations, but not all fluoroquinolone-resistant Mtb isolates have mutations detected. The optimal allele frequency threshold to identify resistance-conferring mutations by whole-genome sequencing is unknown. Methods Phenotypically ofloxacin-resistant and lineage-matched ofloxacin-susceptible Mtb isolates underwent whole-genome sequencing at an average coverage depth of 868 reads. Polymorphisms within the quinolone-resistance–determining region (QRDR) of gyrA and gyrB were identified. The allele frequency threshold using the Genome Analysis Toolkit pipeline was ~8%; allele-level data identified the predominant variant allele frequency and mutational burden (ie, sum of all variant allele frequencies in the QRDR) in gyrA, gyrB, and gyrA + gyrB for each isolate. Receiver operating characteristic (ROC) curves assessed the optimal measure of allele frequency and potential thresholds for identifying phenotypically resistant isolates. Results Of 42 ofloxacin-resistant Mtb isolates, area under the ROC curve (AUC) was highest for predominant variant allele frequency, so that measure was used to evaluate optimal mutation detection thresholds. AUCs for 8%, 2.5%, and 0.8% thresholds were 0.8452, 0.9286, and 0.9069, respectively. Sensitivity and specificity were 69% and 100% for 8%, 86% and 100% for 2.5%, 91% and 91% for 0.8%. The sensitivity of the 2.5% and 0.8% thresholds were significantly higher than the 8% threshold (P = .016 and .004, respectively) but not significantly different between one another (P = .5). Conclusions A predominant mutation allele frequency threshold of 2.5% had the highest AUC for detecting DNA gyrase mutations that confer ofloxacin resistance, and was therefore the optimal threshold.

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