Publications by authors named "Kristin Abbott"

29 Publications

  • Page 1 of 1

CAPICE: a computational method for Consequence-Agnostic Pathogenicity Interpretation of Clinical Exome variations.

Genome Med 2020 08 24;12(1):75. Epub 2020 Aug 24.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Exome sequencing is now mainstream in clinical practice. However, identification of pathogenic Mendelian variants remains time-consuming, in part, because the limited accuracy of current computational prediction methods requires manual classification by experts. Here we introduce CAPICE, a new machine-learning-based method for prioritizing pathogenic variants, including SNVs and short InDels. CAPICE outperforms the best general (CADD, GAVIN) and consequence-type-specific (REVEL, ClinPred) computational prediction methods, for both rare and ultra-rare variants. CAPICE is easily added to diagnostic pipelines as pre-computed score file or command-line software, or using online MOLGENIS web service with API. Download CAPICE for free and open-source (LGPLv3) at https://github.com/molgenis/capice .
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http://dx.doi.org/10.1186/s13073-020-00775-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446154PMC
August 2020

National external quality assessment for next-generation sequencing-based diagnostics of primary immunodeficiencies.

Eur J Hum Genet 2021 Jan 30;29(1):20-28. Epub 2020 Jul 30.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Dutch genome diagnostic centers (GDC) use next-generation sequencing (NGS)-based diagnostic applications for the diagnosis of primary immunodeficiencies (PIDs). The interpretation of genetic variants in many PIDs is complicated because of the phenotypic and genetic heterogeneity. To analyze uniformity of variant filtering, interpretation, and reporting in NGS-based diagnostics for PID, an external quality assessment was performed. Four main Dutch GDCs participated in the quality assessment. Unannotated variant call format (VCF) files of two PID patient analyses per laboratory were distributed among the four GDCs, analyzed, and interpreted (eight analyses in total). Variants that would be reported to the clinician and/or advised for further investigation were compared between the centers. A survey measuring the experiences of clinical laboratory geneticists was part of the study. Analysis of samples with confirmed diagnoses showed that all centers reported at least the variants classified as likely pathogenic (LP) or pathogenic (P) variants in all samples, except for variants in two genes (PSTPIP1 and BTK). The absence of clinical information complicated correct classification of variants. In this external quality assessment, the final interpretation and conclusions of the genetic analyses were uniform among the four participating genetic centers. Clinical and immunological data provided by a medical specialist are required to be able to draw proper conclusions from genetic data.
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http://dx.doi.org/10.1038/s41431-020-0702-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7852558PMC
January 2021

Sexual violence in sport: American Medical Society for Sports Medicine Position Statement.

Br J Sports Med 2021 Feb 18;55(3):132-134. Epub 2020 Jun 18.

Department of Family Medicine and Community Health, University of Minnesota, St Paul, Minnesota, USA.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the Task Force used an iterative process and expert consensus to finalise the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.
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http://dx.doi.org/10.1136/bjsports-2020-102226DOI Listing
February 2021

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

Clin J Sport Med 2020 07;30(4):291-292

Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, Minnesota.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the Position Statement. The objective of this Position Statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.
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http://dx.doi.org/10.1097/JSM.0000000000000855DOI Listing
July 2020

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

Curr Sports Med Rep 2020 Jun;19(6):232-234

Department of Family Medicine and Community Health, University of Minnesota, Minneapolis, MN.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a Position Statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.
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http://dx.doi.org/10.1249/JSR.0000000000000722DOI Listing
June 2020

Sexual Violence in Sport: American Medical Society for Sports Medicine Position Statement.

Sports Health 2020 Jul/Aug;12(4):352-354. Epub 2020 Jun 8.

The American Medical Society for Sports Medicine (AMSSM) convened a group of experts to develop a position statement addressing the problem of sexual violence in sport. The AMSSM Sexual Violence in Sport Task Force held a series of meetings over 7 months, beginning in July 2019. Following a literature review, the task force used an iterative process and expert consensus to finalize the position statement. The objective of this position statement is to raise awareness of this critical issue among sports medicine physicians and to declare a commitment to engage in collaborative, multidisciplinary solutions to reduce sexual violence in sport.
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http://dx.doi.org/10.1177/1941738120929946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787563PMC
July 2020

Injury patterns in synchronized skating: a growing and evolving sport.

J Sports Med Phys Fitness 2020 Apr;60(4):574-581

University of Applied Health Sciences, Zagreb, Croatia.

Background: Data about injuries among synchronized skating athletes are lacking while physical demands in this sport discipline continue to grow. No injury data among junior synchronized skaters exist. The purpose of this study was to investigate the frequency and pattern of injuries in junior and senior synchronized skaters.

Methods: In this descriptive epidemiology study anonymous questionnaires were distributed to synchronized junior and senior skaters. 708 synchronized skaters (393 juniors and 315 seniors) completed the questionnaire. Male skaters were excluded from analysis.

Results: Spinal conditions were reported by 148 (37.7%) juniors compared to 149 (47.3%) of senior skaters with statistically significant cumulative incidence (P=0.01); 23% of juniors and 30.2% of senior skaters reported problems with more than one spinal region; 64.4% juniors and 72.1% senior skaters reported at least one non-spinal injury during their synchronized skating career. There were 380 unique injuries reported by junior skaters and 363 by senior skaters. Lower extremity injuries were the most common injuries in both groups of skaters, followed by upper extremity, head and trunk injuries. From all the anatomical regions mentioned, there was only statistically significant difference between the groups in the occurrence of head injuries with senior skaters having 1.9 greater odds ratio to have head injury.

Conclusions: This study presents new data on the current injury pattern seen in synchronized skating since the inclusion of new skills. The number of head injuries and spinal conditions show statistically significant cumulative incidence in senior compared to junior skaters.
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http://dx.doi.org/10.23736/S0022-4707.19.10249-6DOI Listing
April 2020

GP-provided couple-based expanded preconception carrier screening in the Dutch general population: who accepts the test-offer and why?

Eur J Hum Genet 2020 02 30;28(2):182-192. Epub 2019 Sep 30.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Next generation sequencing has enabled fast and relatively inexpensive expanded carrier screening (ECS) that can inform couples' reproductive decisions before conception and during pregnancy. We previously showed that a couple-based approach to ECS for autosomal recessive (AR) conditions was acceptable and feasible for both health care professionals and the non-pregnant target population in the Netherlands. This paper describes the acceptance of this free test-offer of preconception ECS for 50 severe conditions, the characteristics of test-offer acceptors and decliners, their views on couple-based ECS and reasons for accepting or declining the test-offer. We used a survey that included self-rated health, intention to accept the test-offer, barriers to test-participation and arguments for and against test-participation. Fifteen percent of the expected target population-couples potentially planning a pregnancy-attended pre-test counselling and 90% of these couples proceeded with testing. Test-offer acceptors and decliners differed in their reproductive characteristics (e.g. how soon they wanted to conceive), educational level and stated barriers to test-participation. Sparing a child a life with a severe genetic condition was the most important reason to accept ECS. The most important reason for declining was that the test-result would not affect participants' reproductive decisions. Our results demonstrate that previously uninformed couples of reproductive age, albeit a selective part, were interested in and chose to have couple-based ECS. Alleviating practical barriers, which prevented some interested couples from participating, is recommended before nationwide implementation.
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http://dx.doi.org/10.1038/s41431-019-0516-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6974594PMC
February 2020

Dutch genome diagnostic laboratories accelerated and improved variant interpretation and increased accuracy by sharing data.

Hum Mutat 2019 12 3;40(12):2230-2238. Epub 2019 Sep 3.

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Each year diagnostic laboratories in the Netherlands profile thousands of individuals for heritable disease using next-generation sequencing (NGS). This requires pathogenicity classification of millions of DNA variants on the standard 5-tier scale. To reduce time spent on data interpretation and increase data quality and reliability, the nine Dutch labs decided to publicly share their classifications. Variant classifications of nearly 100,000 unique variants were catalogued and compared in a centralized MOLGENIS database. Variants classified by more than one center were labeled as "consensus" when classifications agreed, and shared internationally with LOVD and ClinVar. When classifications opposed (LB/B vs. LP/P), they were labeled "conflicting", while other nonconsensus observations were labeled "no consensus". We assessed our classifications using the InterVar software to compare to ACMG 2015 guidelines, showing 99.7% overall consistency with only 0.3% discrepancies. Differences in classifications between Dutch labs or between Dutch labs and ACMG were mainly present in genes with low penetrance or for late onset disorders and highlight limitations of the current 5-tier classification system. The data sharing boosted the quality of DNA diagnostics in Dutch labs, an initiative we hope will be followed internationally. Recently, a positive match with a case from outside our consortium resulted in a more definite disease diagnosis.
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http://dx.doi.org/10.1002/humu.23896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900155PMC
December 2019

Improving the diagnostic yield of exome- sequencing by predicting gene-phenotype associations using large-scale gene expression analysis.

Nat Commun 2019 06 28;10(1):2837. Epub 2019 Jun 28.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 VB, Groningen, The Netherlands.

The diagnostic yield of exome and genome sequencing remains low (8-70%), due to incomplete knowledge on the genes that cause disease. To improve this, we use RNA-seq data from 31,499 samples to predict which genes cause specific disease phenotypes, and develop GeneNetwork Assisted Diagnostic Optimization (GADO). We show that this unbiased method, which does not rely upon specific knowledge on individual genes, is effective in both identifying previously unknown disease gene associations, and flagging genes that have previously been incorrectly implicated in disease. GADO can be run on www.genenetwork.nl by supplying HPO-terms and a list of genes that contain candidate variants. Finally, applying GADO to a cohort of 61 patients for whom exome-sequencing analysis had not resulted in a genetic diagnosis, yields likely causative genes for ten cases.
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http://dx.doi.org/10.1038/s41467-019-10649-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599066PMC
June 2019

Feasibility of couple-based expanded carrier screening offered by general practitioners.

Eur J Hum Genet 2019 05 11;27(5):691-700. Epub 2019 Feb 11.

Department of Genetics, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700, RB Groningen, The Netherlands.

Expanded carrier screening (ECS) aims to inform couples' reproductive choice, preferably before conception. As part of an implementation study in which trained general practitioners (GPs) offered a population-based ECS couple-test, we evaluated the feasibility of the test-offer and degree of participant informed choice (IC). Trained GPs from nine practices in the northern Netherlands invited 4295 female patients aged 18-40 to take part in couple-based ECS. Inclusion criteria were having a male partner, planning for children and not being pregnant. We evaluated the feasibility of the organizational aspects, GP competence and the content of the pre-test counselling. Participant satisfaction, evaluation of pre-test counselling and degree of IC were measured using a longitudinal survey. We explored GP experiences and their views on future implementation through semi-structured interviews. 130 consultations took place. All participating GPs were assessed by genetic professionals to be competent to conduct pre-test counselling. Most (63/108 (58%)) consultations took place within the planned 20 min (median 20, IQR 18-28). GPs considered couples' prior knowledge level an important determinant of consultation length. 91% of patients were (very) satisfied with the GP counselling. After pre-test counselling, 231/237(97%) participants had sufficient knowledge and 206/231(88%) had a positive attitude and proceeded with testing. Our pilot demonstrates that offering couple-based ECS through trained and motivated GPs is feasible. Future large-scale implementation requires a well-informed general public and a discussion about appropriate reimbursement for GPs and health care coverage for couples. Providing (more) test information pre-appointment may help reduce average consultation time.
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http://dx.doi.org/10.1038/s41431-019-0351-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462008PMC
May 2019

Care of the Transgender Athlete.

Curr Sports Med Rep 2018 Dec;17(12):410-418

Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.

Transgender individuals identify as a gender different than their sex designated at birth. Transgender athletes, as the name implies, are transgender individuals who participate in sports/athletics. By reviewing the literature relevant to transgender athletes and adding commentary on important considerations, this article acts as a primer for the sports medicine clinician on the care of transgender athletes. We cover terminology, epidemiology, policy, and relevant medical considerations. Literature relevant for medical care specific to transgender athletes is still relatively sparse. We highlight many recommended areas of future research with the potential to make valuable contributions to evidence-based sports medicine practice for this population.
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http://dx.doi.org/10.1249/JSR.0000000000000545DOI Listing
December 2018

Fanconi anaemia presenting as acute myeloid leukaemia and myelodysplastic syndrome in adulthood: a family report on co-occurring FANCC and CHEK2 mutations.

Br J Haematol 2019 03 16;184(6):1071-1073. Epub 2018 May 16.

Department of Haematology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

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http://dx.doi.org/10.1111/bjh.15265DOI Listing
March 2019

Toward an effective exome-based genetic testing strategy in pediatric dilated cardiomyopathy.

Genet Med 2018 11 8;20(11):1374-1386. Epub 2018 Mar 8.

Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.

Purpose: We evaluated the diagnostic yield in pediatric dilated cardiomyopathy (DCM) of combining exome sequencing (ES)-based targeted analysis and genome-wide copy-number variation (CNV) analysis. Based on our findings, we retrospectively designed an effective approach for genetic testing in pediatric DCM.

Methods: We identified 95 patients (in 85 families) with pediatric onset of DCM. We initially excluded 13 of these families because they already had a genetic diagnosis, leaving a total of 31 probands for single-nucleotide polymorphism (SNP) array and trio-ES. We used Human Phenotype Ontology (HPO)-based filtering for our data analysis.

Results: We reached a genetic diagnosis in 15/31 (48.4%) families. ES yielded a diagnosis in 13 probands (13/15; 86.7%), with most variants being found in genes encoding structural cardiomyocyte components. Two large deletions were identified using SNP array. If we had included the 13 excluded families, our estimated yield would have been 54%.

Conclusion: We propose a standardized, stepwise analysis of (i) well-known cardiomyopathy genes, (ii) CNVs, (iii) all genes assigned to HPO cardiomyopathy, and (iv) if appropriate, genes assigned to other HPO terms. This diagnostic approach yields the highest increase at each subsequent step and reduces analytic effort, cost, the number of variants of unknown clinical significance, and the chance of incidental findings.
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http://dx.doi.org/10.1038/gim.2018.9DOI Listing
November 2018

The Effects of Sex Differences and Hormonal Contraception on Outcomes after Collegiate Sports-Related Concussion.

J Neurotrauma 2018 06 27;35(11):1242-1247. Epub 2018 Mar 27.

1 Warren Wright Adolescent Center, Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University , Chicago, Illinois.

There is conflicting evidence regarding whether females are more adversely affected after concussion than males. Further, recent research suggests that hormonal contraceptive (HC) use may affect symptom severity and duration post-concussion. The objective of this study was to examine the effects of sex and HC use on outcomes following concussion among collegiate varsity athletes. We hypothesized that females would have longer length of recovery (LOR), and that peak symptom severity would be associated with longer LOR in both males and females. Among females, we hypothesized that non-HC users would have longer LOR and higher peak symptom severity than HC users. Ninety collegiate student-athletes were included in this study (40 males, 50 females; 24 HC users, 25 non-HC users). Demographic, injury, and recovery information was abstracted via retrospective record review. LOR was defined as days between injury and clearance for full return to play by team physician. Peak symptom severity score (Sport Concussion Assessment Tool [SCAT] 2 or 3) was used in analyses. Study results revealed that males had shorter LOR than females (F[1, 86] = 5.021, p < 0.05, d = 0.49), but had comparable symptom severity scores. Symptom severity was strongly related to LOR for males (r = 0.513, p < 0.01) but not females (r = -0.003, p > 0.05). Among females, non-HC users demonstrated higher symptom severity than HC users (F[1,47] = 5.142, p < 0.05, d = 0.70). No significant differences between female HC users and non-HC users on LOR were observed. This study provides evidence for differential concussion outcomes between male and female collegiate athletes and between HC users and nonusers among females.
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http://dx.doi.org/10.1089/neu.2017.5453DOI Listing
June 2018

Rapid Targeted Genomics in Critically Ill Newborns.

Pediatrics 2017 Oct;140(4)

Department of Genetics, University of Groningen; and.

Background: Rapid diagnostic whole-genome sequencing has been explored in critically ill newborns, hoping to improve their clinical care and replace time-consuming and/or invasive diagnostic testing. A previous retrospective study in a research setting showed promising results with diagnoses in 57%, but patients were highly selected for known and likely Mendelian disorders. The aim of our prospective study was to assess the speed and yield of rapid targeted genomic diagnostics for clinical application.

Methods: We included 23 critically ill children younger than 12 months in ICUs over a period of 2 years. A quick diagnosis could not be made after routine clinical evaluation and diagnostics. Targeted analysis of 3426 known disease genes was performed by using whole-genome sequencing data. We measured diagnostic yield, turnaround times, and clinical consequences.

Results: A genetic diagnosis was obtained in 7 patients (30%), with a median turnaround time of 12 days (ranging from 5 to 23 days). We identified compound heterozygous mutations in the gene (Vici syndrome), the gene (combined oxidative phosphorylation deficiency-11), and the gene (vanishing white matter), and homozygous mutations in the gene (nemaline myopathy), the gene (progressive mitochondrial myopathy), and the gene (GM1-gangliosidosis). In addition, a 1p36.33p36.32 microdeletion was detected in a child with cardiomyopathy.

Conclusions: Rapid targeted genomics combined with copy number variant detection adds important value in the neonatal and pediatric intensive care setting. It led to a fast diagnosis in 30% of critically ill children for whom the routine clinical workup was unsuccessful.
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http://dx.doi.org/10.1542/peds.2016-2854DOI Listing
October 2017

GAVIN: Gene-Aware Variant INterpretation for medical sequencing.

Genome Biol 2017 01 16;18(1). Epub 2017 Jan 16.

University of Groningen, University Medical Center Groningen, Genomics Coordination Center, Groningen, The Netherlands.

We present Gene-Aware Variant INterpretation (GAVIN), a new method that accurately classifies variants for clinical diagnostic purposes. Classifications are based on gene-specific calibrations of allele frequencies from the ExAC database, likely variant impact using SnpEff, and estimated deleteriousness based on CADD scores for >3000 genes. In a benchmark on 18 clinical gene sets, we achieve a sensitivity of 91.4% and a specificity of 76.9%. This accuracy is unmatched by 12 other tools. We provide GAVIN as an online MOLGENIS service to annotate VCF files and as an open source executable for use in bioinformatic pipelines. It can be found at http://molgenis.org/gavin .
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http://dx.doi.org/10.1186/s13059-016-1141-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5240400PMC
January 2017

Population-based preconception carrier screening: how potential users from the general population view a test for 50 serious diseases.

Eur J Hum Genet 2016 10 11;24(10):1417-23. Epub 2016 May 11.

Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

With the increased international focus on personalized health care and preventive medicine, next-generation sequencing (NGS) has substantially expanded the options for carrier screening of serious, recessively inherited diseases. NGS screening tests not only offer reproductive options not previously available to couples, but they may also ultimately reduce the number of children born with devastating disorders. To date, preconception carrier screening (PCS) has largely targeted single diseases such as cystic fibrosis, but NGS allows the testing of many genes or diseases simultaneously. We have developed an expanded NGS PCS test for couples; simultaneously it covers 50 very serious, early-onset, autosomal recessive diseases that are untreatable. This is the first, noncommercial, population-based, expanded PCS test to be offered prospectively to couples in a health-care setting in Europe. So far, little is known about how potential users view such a PCS test. We therefore performed an online survey in 2014 among 500 people from the target population in the Netherlands. We enquired about their intention to take an expanded PCS test if one was offered, and through which provider they would like to see it offered. One-third of the respondents said they would take such a test were it to be offered. The majority (44%) preferred the test to be offered via their general practitioner (GP) and 58% would be willing to pay for the test, with a median cost of [euro ]75. Our next step is to perform an implementation study in which this PCS test will be provided via selected GPs in the Northern Netherlands.
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http://dx.doi.org/10.1038/ejhg.2016.43DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5027688PMC
October 2016

Calling genotypes from public RNA-sequencing data enables identification of genetic variants that affect gene-expression levels.

Genome Med 2015 27;7(1):30. Epub 2015 Mar 27.

University of Groningen, University Medical Center Groningen, Department of Genetics, 9700 RB Groningen, The Netherlands.

Background: RNA-sequencing (RNA-seq) is a powerful technique for the identification of genetic variants that affect gene-expression levels, either through expression quantitative trait locus (eQTL) mapping or through allele-specific expression (ASE) analysis. Given increasing numbers of RNA-seq samples in the public domain, we here studied to what extent eQTLs and ASE effects can be identified when using public RNA-seq data while deriving the genotypes from the RNA-sequencing reads themselves.

Methods: We downloaded the raw reads for all available human RNA-seq datasets. Using these reads we performed gene expression quantification. All samples were jointly normalized and subjected to a strict quality control. We also derived genotypes using the RNA-seq reads and used imputation to infer non-coding variants. This allowed us to perform eQTL mapping and ASE analyses jointly on all samples that passed quality control. Our results were validated using samples for which DNA-seq genotypes were available.

Results: 4,978 public human RNA-seq runs, representing many different tissues and cell-types, passed quality control. Even though these data originated from many different laboratories, samples reflecting the same cell type clustered together, suggesting that technical biases due to different sequencing protocols are limited. In a joint analysis on the 1,262 samples with high quality genotypes, we identified cis-eQTLs effects for 8,034 unique genes (at a false discovery rate ≤0.05). eQTL mapping on individual tissues revealed that a limited number of samples already suffice to identify tissue-specific eQTLs for known disease-associated genetic variants. Additionally, we observed strong ASE effects for 34 rare pathogenic variants, corroborating previously observed effects on the corresponding protein levels.

Conclusions: By deriving and imputing genotypes from RNA-seq data, it is possible to identify both eQTLs and ASE effects. Given the exponential growth of the number of publicly available RNA-seq samples, we expect this approach will become especially relevant for studying the effects of tissue-specific and rare pathogenic genetic variants to aid clinical interpretation of exome and genome sequencing.
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http://dx.doi.org/10.1186/s13073-015-0152-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4423486PMC
May 2015

Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization.

Hum Mutat 2015 Jul 20;36(7):712-9. Epub 2015 May 20.

Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Next-generation sequencing in clinical diagnostics is providing valuable genomic variant data, which can be used to support healthcare decisions. In silico tools to predict pathogenicity are crucial to assess such variants and we have evaluated a new tool, Combined Annotation Dependent Depletion (CADD), and its classification of gene variants in Lynch syndrome by using a set of 2,210 DNA mismatch repair gene variants. These had already been classified by experts from InSiGHT's Variant Interpretation Committee. Overall, we found CADD scores do predict pathogenicity (Spearman's ρ = 0.595, P < 0.001). However, we discovered 31 major discrepancies between the InSiGHT classification and the CADD scores; these were explained in favor of the expert classification using population allele frequencies, cosegregation analyses, disease association studies, or a second-tier test. Of 751 variants that could not be clinically classified by InSiGHT, CADD indicated that 47 variants were worth further study to confirm their putative pathogenicity. We demonstrate CADD is valuable in prioritizing variants in clinically relevant genes for further assessment by expert classification teams.
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http://dx.doi.org/10.1002/humu.22798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973827PMC
July 2015

Injuries in women's ice hockey: special considerations.

Authors:
Kristin Abbott

Curr Sports Med Rep 2014 Nov-Dec;13(6):377-82

Northwestern University, Evanston, IL.

Ice hockey is a popular collision sport with a growing number of female athletes participating each year. As participation among girls and women continues to increase, it will be important to recognize common injuries occurring during women's games. Despite difference in the rules that prohibit body checking in women's and girls' games, injury profiles are similar to those of their male counterparts. Concussions, contusions, acromioclavicular joint injuries, ligamentous knee injuries, and muscle strains occur during women's ice hockey games, with groin strains accounting for the most common practice injury. This article will review both injury rates and common injuries occurring in women's ice hockey, with a focus on the observed concussion rate and groin injuries.
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http://dx.doi.org/10.1249/JSR.0000000000000102DOI Listing
July 2015

Medical issues in synchronized skating.

Curr Sports Med Rep 2013 Nov-Dec;12(6):391-6

1 Northwestern University Health Service, IL; and 2 Primary Care Sports Medicine Fellowship, Department of Family Medicine and Community Health, University of Minnesota, 2525 University Ave SE, Minneapolis, MN.

Synchronized skating is a unique sport of team skating and currently represents the largest competitive discipline in U.S. Figure Skating. Synchronized skating allows skaters to compete as part of a team with opportunities to represent their country in international competitions. As the popularity of the sport continues to grow, more of these athletes will present to sports medicine clinics with injuries and illnesses related to participation in synchronized skating. The purpose of this article is to review the common injuries and medical conditions affecting synchronized skaters.
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http://dx.doi.org/10.1249/JSR.0000000000000010DOI Listing
July 2014

Testing for post-copulatory selection for major histocompatibility complex genotype in a semi-free-ranging primate population.

Am J Primatol 2013 Oct 15;75(10):1021-31. Epub 2013 May 15.

Evolutionary Anthropology Research Group, Department of Anthropology, Durham University, Durham, United Kingdom.

A large body of evidence suggests that major histocompatibility complex (MHC) genotype influences mate choice. However, few studies have investigated MHC-mediated post-copulatory mate choice under natural, or even semi-natural, conditions. We set out to explore this question in a large semi-free-ranging population of mandrills (Mandrillus sphinx) using MHC-DRB genotypes for 127 parent-offspring triads. First, we showed that offspring MHC heterozygosity correlates positively with parental MHC dissimilarity suggesting that mating among MHC dissimilar mates is efficient in increasing offspring MHC diversity. Second, we compared the haplotypes of the parental dyad with those of the offspring to test whether post-copulatory sexual selection favored offspring with two different MHC haplotypes, more diverse gamete combinations, or greater within-haplotype diversity. Limited statistical power meant that we could only detect medium or large effect sizes. Nevertheless, we found no evidence for selection for heterozygous offspring when parents share a haplotype (large effect size), genetic dissimilarity between parental haplotypes (we could detect an odds ratio of ≥1.86), or within-haplotype diversity (medium-large effect). These findings suggest that comparing parental and offspring haplotypes may be a useful approach to test for post-copulatory selection when matings cannot be observed, as is the case in many study systems. However, it will be extremely difficult to determine conclusively whether post-copulatory selection mechanisms for MHC genotype exist, particularly if the effect sizes are small, due to the difficulty in obtaining a sufficiently large sample.
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http://dx.doi.org/10.1002/ajp.22166DOI Listing
October 2013

Exonic deletions in AUTS2 cause a syndromic form of intellectual disability and suggest a critical role for the C terminus.

Am J Hum Genet 2013 Feb 17;92(2):210-20. Epub 2013 Jan 17.

Department of Clinical Genetics, VU University Medical Center, Amsterdam 1007 MB, The Netherlands.

Genomic rearrangements involving AUTS2 (7q11.22) are associated with autism and intellectual disability (ID), although evidence for causality is limited. By combining the results of diagnostic testing of 49,684 individuals, we identified 24 microdeletions that affect at least one exon of AUTS2, as well as one translocation and one inversion each with a breakpoint within the AUTS2 locus. Comparison of 17 well-characterized individuals enabled identification of a variable syndromic phenotype including ID, autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. The dysmorphic features were more pronounced in persons with 3'AUTS2 deletions. This part of the gene is shown to encode a C-terminal isoform (with an alternative transcription start site) expressed in the human brain. Consistent with our genetic data, suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the C-terminal isoform of AUTS2. Our observations demonstrate a causal role of AUTS2 in neurocognitive disorders, establish a hitherto unappreciated syndromic phenotype at this locus, and show how transcriptional complexity can underpin human pathology. The zebrafish model provides a valuable tool for investigating the etiology of AUTS2 syndrome and facilitating gene-function analysis in the future.
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http://dx.doi.org/10.1016/j.ajhg.2012.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3567268PMC
February 2013

Ring chromosome 12 with inverted microduplication of 12p13.3 involving the Von Willebrand Factor gene associated with cryptogenic stroke in a young adult male.

Eur J Med Genet 2011 Jan-Feb;54(1):97-101. Epub 2010 Oct 8.

We report a 35-year-old male with a ring chromosome 12 originally diagnosed 20 years prior to presentation with an ischemic stroke. Array CGH analysis revealed a sub-microscopic microdeletion and microduplication within 12p13.3 and a microdeletion in 12q24.33. FISH analysis further revealed that the duplication was in an inverted orientation and included exons 35-52 of the dosage-sensitive Von Willebrand Factor (VWF) gene. Partial duplication of this gene, which has a role in the clotting cascade, suggests a potential mechanism for generating a pro-thrombotic state that may have contributed to a premature cerebrovascular event. Evidence of raised VWF antigen levels and VWF activity levels in the highest quartile provides support for this hypothesis. This case illustrates that when a ring chromosome is identified, the possibility of cryptic genomic rearrangements needs to be considered as these may have implications in predicting natural history.
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http://dx.doi.org/10.1016/j.ejmg.2010.09.014DOI Listing
June 2011

Odour signals major histocompatibility complex genotype in an Old World monkey.

Proc Biol Sci 2011 Jan 4;278(1703):274-80. Epub 2010 Aug 4.

Department of Anthropology, University of Durham, South Road, Durham DH1 3LE, UK.

The major histocompatibility complex (MHC) is an extraordinarily diverse cluster of genes that play a key role in the immune system. MHC gene products are also found in various body secretions, leading to the suggestion that MHC genotypes are linked to unique individual odourtypes that animals use to assess the suitability of other individuals as potential mates or social partners. We investigated the relationship between chemical odour profiles and genotype in a large, naturally reproducing population of mandrills, using gas chromatography-mass spectrometry and MHC genotyping. Odour profiles were not linked to the possession of particular MHC supertypes. Sex influenced some measures of odour diversity and dominance rank influenced some measures of odour diversity in males, but not in females. Odour similarity was strongly related to similarity at the MHC, and, in some cases, to pedigree relatedness. Our results suggest that odour provides both a cue of individual genetic quality and information against which the receiver can compare its own genotype to assess genetic similarity. These findings provide a potential mechanism underlying mate choice for genetic diversity and MHC similarity as well as kin selection.
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http://dx.doi.org/10.1098/rspb.2010.0571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3013381PMC
January 2011

A de novo 4q34 interstitial deletion of at least 9.3 Mb with no discernible phenotypic effect.

Am J Med Genet A 2010 Jul;152A(7):1764-9

Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, United Kingdom.

Cytogenetically visible imbalances without phenotypic effect are still rare despite the extent of large-scale copy number variation in the normal population revealed by array CGH. Here we report on a phenotypically normal 30-year-old female with a de novo, cytogenetically visible, interstitial deletion of band 4q34. She was referred following three successive miscarriages, one of which was an intra-uterine death with subendocardial fibroelastosis and dilated cardiomyopathy. There was no other notable medical or family history, she was of normal intelligence and had no dysmorphic features. FISH and Array CGH with a customized 1 Mb BAC array showed that the deletion is a minimum of 9.3 and a maximum of 10.7 Mb in size, between approximately 173 Mb in 4q34.1 and approximately 182 Mb in 4q34.3. The deletion contains only 23 known coding genes giving a low average gene density of approximately 2 genes/Mb. This case further illustrates that (1) sizeable imbalances can be associated with apparent phenotypic normality, (2) gene density is a better guide to possible phenotypic consequences than aberration size, and (3) it is not always safe to assume that de novo imbalances will be causal.
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http://dx.doi.org/10.1002/ajmg.a.33426DOI Listing
July 2010

A de novo duplication of Xp11.22-p11.4 in a girl with intellectual disability, structural brain anomalies, and preferential inactivation of the normal X chromosome.

Am J Med Genet A 2010 Jul;152A(7):1735-40

Department of Clinical Genetics, Guy's Hospital, London, UK.

Only a small number of individuals with duplications within the proximal short arm of the X chromosome have been reported. The majority of patients have duplications encompassing Xp11-p21, or extend more distally into Xp22. We report on a female patient who presented within the first year of life with plagiocephaly, speech delay, and epilepsy. Brain MRI showed a relatively thin cerebral cortex, abnormal periventricular white matter, and abnormal vessels in the left inferior parietal region. Cytogenetic and microsatellite analysis of the patient and her parents showed that she has a de novo duplication of Xp11.22-Xp11.4 on her paternal X chromosome. FISH analysis using fluorescently labeled BACs followed by array analysis including an X tilepath BAC array showed that a 12.3 Mb interval between 40.4 Mb and 52.7 Mb from the Xp telomere (NCBI build 36) was duplicated and excluded the presence of additional rearrangements along the X chromosome. Interestingly, X-inactivation studies in peripheral blood leukocytes showed that the duplicated (paternal) X chromosome was active in the majority of cells, in contrast to other patients with Xp duplications in whom X inactivation is random or skewed toward the normal X. These findings suggest that overexpression of genes from proximal Xp is likely to have contributed to her clinical phenotype.
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http://dx.doi.org/10.1002/ajmg.a.33457DOI Listing
July 2010

High levels of diversity characterize mandrill (Mandrillus sphinx) Mhc-DRB sequences.

Immunogenetics 2006 Aug 27;58(8):628-40. Epub 2006 Jun 27.

PrIME, Department of Biological Anthropology, University of Cambridge, Downing Street, Cambridge, CB2 3DZ, UK.

The major histocompatibility complex (MHC) is highly polymorphic in most primate species studied thus far. The rhesus macaque (Macaca mulatta) has been studied extensively and the Mhc-DRB region demonstrates variability similar to humans. The extent of MHC diversity is relatively unknown for other Old World monkeys (OWM), especially among genera other than Macaca. A molecular survey of the Mhc-DRB region in mandrills (Mandrillus sphinx) revealed extensive variability, suggesting that other OWMs may also possess high levels of Mhc-DRB polymorphism. In the present study, 33 Mhc-DRB loci were identified from only 13 animals. Eleven were wild-born and presumed to be unrelated and two were captive-born twins. Two to seven different sequences were identified for each individual, suggesting that some mandrills may have as many as four Mhc-DRB loci on a single haplotype. From these sequences, representatives of at least six Mhc-DRB loci or lineages were identified. As observed in other primates, some new lineages may have arisen through the process of gene conversion. These findings indicate that mandrills have Mhc-DRB diversity not unlike rhesus macaques and humans.
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http://dx.doi.org/10.1007/s00251-006-0132-3DOI Listing
August 2006