Publications by authors named "Sophia Peters"

13 Publications

  • Page 1 of 1

Total Femoral Replacement- A Case Report.

Geriatr Orthop Surg Rehabil 2021 18;12:21514593211019977. Epub 2021 Jun 18.

Department of Surgery, University of Toronto, Scarborough Health Network, Ontario, Canada.

Total femoral replacement(TFR) is a well-recognized salvage procedure performed after multiple failed endoprosthetic replacements, which result in severely compromised bone stock and damaged structural integrity. TFR is performed as an alternative to lower limb amputation, restoring femoral integrity and enabling patients to resume ambulation. TFR is expected to be performed more frequently as the worldwide rate of revision arthroplasty increases due to improved patient survival rates and their underlying diseases, exceeding the functional life of endoprosthetic arthroplasty. We present a 74-year-old, overweight woman with an extensive surgical history with respect to her right knee. Her right lower extremity x-rays showed a long-cemented stem knee tumour prosthesis and a Garden 4 subcapital fracture of the ipsilateral hip. Due to multiple surgeries of the knee and femur in the past, a total femoral replacement was required to be performed. The procedure was successful, and the expected outcome was met. A successful procedure performed by a skilled and experienced surgical team, a thorough rehabilitation program, and prompt post-operative management of complications, can overcome the high incidence of infection and dislocation to preserve the limb with improved functionality and reduce pain. TFR is a drastic operative intervention that can preserve the quality of life for most patients.
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http://dx.doi.org/10.1177/21514593211019977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216370PMC
June 2021

TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19.

NPJ Genom Med 2021 Jul 1;6(1):55. Epub 2021 Jul 1.

Neonatology and Pediatric Intensive Care, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany.

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.
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http://dx.doi.org/10.1038/s41525-021-00220-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249618PMC
July 2021

Two Faces of Vitamin C in Hemodialysis Patients: Relation to Oxidative Stress and Inflammation.

Nutrients 2021 Feb 27;13(3). Epub 2021 Feb 27.

Department of Nephrology, Hypertension, and Kidney Transplantation, Medical University of Lodz, ul. Pomorska 251, 92-213 Lodz, Poland.

Hemodialysis (HD) is the most common method of renal replacement therapy. Besides toxins, it eliminates nutrients from the circulation, such as ascorbic acid (AA). HD-patients present AA deficiency more often than representatives of the general population, also due to dietary restrictions. This condition aggravates oxidative stress and inflammation related to uremia and extracorporeal circulation and increases cardiovascular risk followed by mortality. Supplementation of AA seems to be a promising approach in the treatment of hemodialysis patients. Many successful interventions restored plasma AA concentration in HD patients by enteral or intravenous supplementation, concomitantly inhibiting oxidative stress and inflammation. A significant number of studies reported opposite, serious pro-oxidant effects of AA. In this narrative review, we present studies, commenting on their limitations; on AA plasma or serum concentration and the influence of its supplementation on protein and lipid peroxidation, DNA damage, reactive oxygen species generation, paraoxonase activity, advanced glycation endproducts, and C-reactive protein (CRP) concentration. Moreover, in terms of safety, the possible development of oxalosis in HD patients regarding the intravenous or enteral route of AA administration is discussed. Unequivocal clinical results of recent studies on hemodialysis patients are displayed.
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http://dx.doi.org/10.3390/nu13030791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997461PMC
February 2021

Nine newly identified individuals refine the phenotype associated with MYT1L mutations.

Am J Med Genet A 2020 05 17;182(5):1021-1031. Epub 2020 Feb 17.

Institute of Human Genetics, University of Bonn, University Hospital Bonn, Bonn, Germany.

Both point mutations and deletions of the MYT1L gene as well as microdeletions of chromosome band 2p25.3 including MYT1L are associated with intellectual disability, obesity, and behavioral problems. Thus, MYT1L is assumed to be the-at least mainly-causative gene in the 2p25.3 deletion syndrome. Here, we present comprehensive descriptions of nine novel individuals bearing MYT1L mutations; most of them single nucleotide variants (SNVs). This increases the number of known individuals with causative deletions or SNVs of MYT1L to 51. Since eight of the nine novel patients bear mutations affecting MYT1L only, the total number of such individuals now nearly equals the number of individuals with larger microdeletions affecting additional genes, allowing for a comprehensive phenotypic comparison of these two patient groups. For example, 55% of the individuals with mutations affecting MYT1L only were overweight or obese as compared to 86% of the individuals with larger microdeletions. A similar trend was observed regarding short stature with 5 versus 35%, respectively. However, these differences were nominally significant only after correction for multiple testing, further supporting the hypothesis that MYT1L haploinsufficiency is central to the 2p25.3 deletion phenotype. Most importantly, the large number of individuals with MYT1L mutations presented and reviewed here allowed for the delineation of a more comprehensive clinical picture. Seizures, postnatal short stature, macrocephaly, and microcephaly could be shown to be over-represented among individuals with MYT1L mutations.
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http://dx.doi.org/10.1002/ajmg.a.61515DOI Listing
May 2020

Diagnostic yield and clinical utility of a comprehensive gene panel for hereditary tumor syndromes.

Hered Cancer Clin Pract 2019 23;17. Epub 2019 Jan 23.

1Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany.

Background: In a considerable number of patients with a suspected hereditary tumor syndrome (HTS), no underlying germline mutation is detected in the most likely affected genes. The present study aimed to establish and validate a large gene panel for HTS, and determine its diagnostic yield and clinical utility.

Methods: The study cohort comprised 173 patients with suspected, but unexplained, HTS (group U) and 64 HTS patients with a broad spectrum of known germline mutations (group K). All patients in group U presented with early age at onset, multiple tumors, and/or a familial clustering of various tumor types; no germline mutation had been identified during routine diagnostics. Sequencing of leukocyte DNA was performed for the 94 HTS genes of the Illumina TruSight™Cancer Panel and 54 additional HTS genes.

Results: The sensitivity of the panel to identify known germline variants was 99.6%. In addition to known mutations, a total of 192 rare, potentially pathogenic germline variants in 86 genes were identified. Neither the proportion of rare variants per patient (group K: 0.9 variants; group U: 0.8 variants) nor the proportion of variants in the most frequently mutated, moderately penetrant genes and showed significant inter-group difference. Four of the five patients from group U with a truncating mutation had thyroid cancer, pointing to a broader tumor spectrum in patients with pathogenic variants. In 22% of patients from group K, a further potential causative variant was identified. Here, the most interesting finding was an nonsense mutation in a child with a known frameshift mutation In 17% of patients from group U, potential causative variants were identified. In three of these patients (2%), mutations in , or were considered to be causative. In both groups, incidental findings with presumptive predictive value were generated.

Conclusions: The gene panel identified the genetic cause in some prescreened, unexplained HTS patients and generated incidental findings. Some patients harbored predicted pathogenic mutations in more than one established HTS gene, rendering interpretation of the respective alterations challenging. Established moderate risk genes showed an almost equal distribution among patients with known and unexplained disease.
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http://dx.doi.org/10.1186/s13053-018-0102-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6343270PMC
January 2019

Basal cell carcinomas developing independently from BAP1-tumor predisposition syndrome in a patient with bilateral uveal melanoma: Diagnostic challenges to identify patients with BAP1-TPDS.

Genes Chromosomes Cancer 2019 06 23;58(6):357-364. Epub 2019 Jan 23.

Department of Ophthalmology, Division of Ophthalmic Pathology, University Hospital Bonn, Bonn, Germany.

Basal cell carcinomas (BCC) have been recently included into the spectrum of BAP1-tumor predisposition syndrome (TPDS). Uveal melanoma (UM) is also a tumor often observed in patients with this hereditary tumor syndrome, in particular bilateral UM is highly suspicious for BAP1-TPDS although no patient has been reported yet. Based on our index patient with BAP1-TPDS with bilateral UM (choroid OD, oculus dexter; iris OS, oculus sinister), several BCCs and thyroid cancer as well as a family history for cancer, this paper analyzes hints and pitfalls to diagnose this syndrome clinically and histologically. A previously undescribed germline variant, namely a heterozygous deletion of a single nucleotide on position 2001 (c.2001delG;p.[Thr668Profs*24] in exon 16 of the BAP1 gene), was identified. Structural changes in the C-terminal of the BAP1 protein were observed by in silico analysis. While the excised iris melanoma showed loss of BAP1 nuclear staining by immunohistochemical staining, the BCCs of our patient (and in the control group, n = 13) were BAP1 positive. Genetic analysis of the BCC of the ocular adnexae confirmed a remaining intact BAP1 copy. The constellation of (bilateral) UM in combination with BCC should raise suspicion for a BAP1-TPDS. As our BCCs probably developed independently from the BAP1-TPDS and UMs frequently show loss of nuclear BAP1 staining, genetic analysis is mandatory to diagnose this syndrome.
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http://dx.doi.org/10.1002/gcc.22724DOI Listing
June 2019

Copy number variation analysis and targeted NGS in 77 families with suspected Lynch syndrome reveals novel potential causative genes.

Int J Cancer 2018 12 3;143(11):2800-2813. Epub 2018 Oct 3.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

In many families with suspected Lynch syndrome (LS), no germline mutation in the causative mismatch repair (MMR) genes is detected during routine diagnostics. To identify novel causative genes for LS, the present study investigated 77 unrelated, mutation-negative patients with clinically suspected LS and a loss of MSH2 in tumor tissue. An analysis for genomic copy number variants (CNV) was performed, with subsequent next generation sequencing (NGS) of selected candidate genes in a subgroup of the cohort. Genomic DNA was genotyped using Illumina's HumanOmniExpress Bead Array. After quality control and filtering, 25 deletions and 16 duplications encompassing 73 genes were identified in 28 patients. No recurrent CNV was detected, and none of the CNVs affected the regulatory regions of MSH2. A total of 49 candidate genes from genomic regions implicated by the present CNV analysis and 30 known or assumed risk genes for colorectal cancer (CRC) were then sequenced in a subset of 38 patients using a customized NGS gene panel and Sanger sequencing. Single nucleotide variants were identified in 14 candidate genes from the CNV analysis. The most promising of these candidate genes were: (i) PRKCA, PRKDC, and MCM4, as a functional relation to MSH2 is predicted by network analysis, and (ii) CSMD1, as this is commonly mutated in CRC. Furthermore, six patients harbored POLE variants outside the exonuclease domain, suggesting that these might be implicated in hereditary CRC. Analyses in larger cohorts of suspected LS patients recruited via international collaborations are warranted to verify the present findings.
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http://dx.doi.org/10.1002/ijc.31725DOI Listing
December 2018

De novo FBXO11 mutations are associated with intellectual disability and behavioural anomalies.

Hum Genet 2018 May 23;137(5):401-411. Epub 2018 May 23.

Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

Intellectual disability (ID) has an estimated prevalence of 1.5-2%. In most affected individuals, its genetic basis remains unclear. Whole exome sequencing (WES) studies have identified a multitude of novel causative gene defects and have shown that a large proportion of sporadic ID cases results from de novo mutations. Here, we present two unrelated individuals with similar clinical features and deleterious de novo variants in FBXO11 detected by WES. Individual 1, a 14-year-old boy, has mild ID as well as mild microcephaly, corrected cleft lip and alveolus, hyperkinetic disorder, mild brain atrophy and minor facial dysmorphism. WES detected a heterozygous de novo 1 bp insertion in the splice donor site of exon 3. Individual 2, a 3-year-old boy, showed ID and pre- and postnatal growth retardation, postnatal mild microcephaly, hyperkinetic and restless behaviour, as well as mild dysmorphism. WES detected a heterozygous de novo frameshift mutation. While ten individuals with ID and de novo variants in FBXO11 have been reported as part of larger studies, only one of the reports has some additional clinical data. Interestingly, the latter individual carries the identical mutation as our individual 2 and also displays ID, intrauterine growth retardation, microcephaly, behavioural anomalies, and dysmorphisms. Thus, we confirm deleterious de novo mutations in FBXO11 as a cause of ID and start the delineation of the associated clinical picture which may also comprise postnatal microcephaly or borderline small head size and behavioural anomalies.
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http://dx.doi.org/10.1007/s00439-018-1892-1DOI Listing
May 2018

Exome sequencing characterizes the somatic mutation spectrum of early serrated lesions in a patient with serrated polyposis syndrome (SPS).

Hered Cancer Clin Pract 2017 29;15:22. Epub 2017 Nov 29.

Institute of Human Genetics, University of Bonn, Bonn, Germany.

Background: Serrated or Hyperplastic Polyposis Syndrome (SPS, HPS) is a yet poorly defined colorectal cancer (CRC) predisposition characterised by the occurrence of multiple and/or large serrated polyps throughout the colon. A serrated polyp-CRC sequence (serrated pathway) of CRC formation has been postulated, however, to date only few molecular signatures of serrated neoplasia (, mutations, CpG Island Methylation, MSI) have been described in a subset of SPS patients and neither the etiology of the syndrome nor the distinct genetic alterations during tumorigenesis have been identified.

Methods: To identify somatic point mutations in potential novel candidate genes of SPS-associated lesions and the involved pathways we performed exome sequencing of eleven early serrated polyps obtained from a 41 year-old female patient with clinically confirmed SPS. For data filtering and analysis, standard pipelines were used. Somatic mutations were identified by comparison with leukocyte DNA and were validated by Sanger sequencing.

Results: The p.V600E or p.G12D mutation was identified in six polyps (~50%) and not found in polyps from the distal colon. In addition, we found seven unique rare somatic alterations of seven different genes in four serrated tumours, all of which are missense variants. The variant in and are predicted to be deleterious No established cancer gene or candidate genes related to serrated tumorigenesis were affected.

Conclusions: Somatic mutations seem to be rare events in early hyperplastic and serrated lesions of SPS patients. Neither frequently affected genes nor enrichment of specific pathways were observed. Thus, other alterations such as non-coding variants or epigenetic changes might be the major driving force of tumour progression in SPS.
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http://dx.doi.org/10.1186/s13053-017-0082-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5707812PMC
November 2017

Genomic and transcriptomic heterogeneity of colorectal tumours arising in Lynch syndrome.

J Pathol 2017 10 5;243(2):242-254. Epub 2017 Sep 5.

Institute of Pathology, Centre for Integrated Oncology, University Hospital Cologne, Cologne, Germany.

Colorectal cancer (CRC) arising in Lynch syndrome (LS) comprises tumours with constitutional mutations in DNA mismatch repair genes. There is still a lack of whole-genome and transcriptome studies of LS-CRC to address questions about similarities and differences in mutation and gene expression characteristics between LS-CRC and sporadic CRC, about the molecular heterogeneity of LS-CRC, and about specific mechanisms of LS-CRC genesis linked to dysfunctional mismatch repair in LS colonic mucosa and the possible role of immune editing. Here, we provide a first molecular characterization of LS tumours and of matched tumour-distant reference colonic mucosa based on whole-genome DNA-sequencing and RNA-sequencing analyses. Our data support two subgroups of LS-CRCs, G1 and G2, whereby G1 tumours show a higher number of somatic mutations, a higher amount of microsatellite slippage, and a different mutation spectrum. The gene expression phenotypes support this difference. Reference mucosa of G1 shows a strong immune response associated with the expression of HLA and immune checkpoint genes and the invasion of CD4+ T cells. Such an immune response is not observed in LS tumours, G2 reference and normal (non-Lynch) mucosa, and sporadic CRC. We hypothesize that G1 tumours are edited for escape from a highly immunogenic microenvironment via loss of HLA presentation and T-cell exhaustion. In contrast, G2 tumours seem to develop in a less immunogenic microenvironment where tumour-promoting inflammation parallels tumourigenesis. Larger studies on non-neoplastic mucosa tissue of mutation carriers are required to better understand the early phases of emerging tumours. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4948DOI Listing
October 2017

Exome Sequencing Identifies Biallelic MSH3 Germline Mutations as a Recessive Subtype of Colorectal Adenomatous Polyposis.

Am J Hum Genet 2016 Aug 28;99(2):337-51. Epub 2016 Jul 28.

Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Center for Hereditary Tumor Syndromes, University of Bonn, 53127 Bonn, Germany. Electronic address:

In ∼30% of families affected by colorectal adenomatous polyposis, no germline mutations have been identified in the previously implicated genes APC, MUTYH, POLE, POLD1, and NTHL1, although a hereditary etiology is likely. To uncover further genes with high-penetrance causative mutations, we performed exome sequencing of leukocyte DNA from 102 unrelated individuals with unexplained adenomatous polyposis. We identified two unrelated individuals with differing compound-heterozygous loss-of-function (LoF) germline mutations in the mismatch-repair gene MSH3. The impact of the MSH3 mutations (c.1148delA, c.2319-1G>A, c.2760delC, and c.3001-2A>C) was indicated at the RNA and protein levels. Analysis of the diseased individuals' tumor tissue demonstrated high microsatellite instability of di- and tetranucleotides (EMAST), and immunohistochemical staining illustrated a complete loss of nuclear MSH3 in normal and tumor tissue, confirming the LoF effect and causal relevance of the mutations. The pedigrees, genotypes, and frequency of MSH3 mutations in the general population are consistent with an autosomal-recessive mode of inheritance. Both index persons have an affected sibling carrying the same mutations. The tumor spectrum in these four persons comprised colorectal and duodenal adenomas, colorectal cancer, gastric cancer, and an early-onset astrocytoma. Additionally, we detected one unrelated individual with biallelic PMS2 germline mutations, representing constitutional mismatch-repair deficiency. Potentially causative variants in 14 more candidate genes identified in 26 other individuals require further workup. In the present study, we identified biallelic germline MSH3 mutations in individuals with a suspected hereditary tumor syndrome. Our data suggest that MSH3 mutations represent an additional recessive subtype of colorectal adenomatous polyposis.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974087PMC
August 2016

Exome sequencing identifies potential novel candidate genes in patients with unexplained colorectal adenomatous polyposis.

Fam Cancer 2016 Apr;15(2):281-8

Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany.

In up to 30% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, and POLE or POLD1, causing Polymerase-Proofreading-associated polyposis can be identified, although a hereditary etiology is likely. To uncover new causative genes, exome sequencing was performed using DNA from leukocytes and a total of 12 colorectal adenomas from seven unrelated patients with unexplained sporadic adenomatous polyposis. For data analysis and variant filtering, an established bioinformatics pipeline including in-house tools was applied. Variants were filtered for rare truncating point mutations and copy-number variants assuming a dominant, recessive, or tumor suppressor model of inheritance. Subsequently, targeted sequence analysis of the most promising candidate genes was performed in a validation cohort of 191 unrelated patients. All relevant variants were validated by Sanger sequencing. The analysis of exome sequencing data resulted in the identification of rare loss-of-function germline mutations in three promising candidate genes (DSC2, PIEZO1, ZSWIM7). In the validation cohort, further variants predicted to be pathogenic were identified in DSC2 and PIEZO1. According to the somatic mutation spectra, the adenomas in this patient cohort follow the classical pathways of colorectal tumorigenesis. The present study identified three candidate genes which might represent rare causes for a predisposition to colorectal adenoma formation. Especially PIEZO1 (FAM38A) and ZSWIM7 (SWS1) warrant further exploration. To evaluate the clinical relevance of these genes, investigation of larger patient cohorts and functional studies are required.
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http://dx.doi.org/10.1007/s10689-016-9870-zDOI Listing
April 2016

Low-level APC mutational mosaicism is the underlying cause in a substantial fraction of unexplained colorectal adenomatous polyposis cases.

J Med Genet 2016 Mar 27;53(3):172-9. Epub 2015 Nov 27.

Institute of Human Genetics, University of Bonn, Bonn, Germany Center for Hereditary Tumor Syndromes, University of Bonn, Bonn, Germany.

Background: In 30-50% of patients with colorectal adenomatous polyposis, no germline mutation in the known genes APC, causing familial adenomatous polyposis, MUTYH, causing MUTYH-associated polyposis, or POLE or POLD1, causing polymerase-proofreading-associated polyposis can be identified, although a hereditary aetiology is likely. This study aimed to explore the impact of APC mutational mosaicism in unexplained polyposis.

Methods: To comprehensively screen for somatic low-level APC mosaicism, high-coverage next-generation sequencing of the APC gene was performed using DNA from leucocytes and a total of 53 colorectal tumours from 20 unrelated patients with unexplained sporadic adenomatous polyposis. APC mosaicism was assumed if the same loss-of-function APC mutation was present in ≥ 2 anatomically separated colorectal adenomas/carcinomas per patient. All mutations were validated using diverse methods.

Results: In 25% (5/20) of patients, somatic mosaicism of a pathogenic APC mutation was identified as underlying cause of the disease. In 2/5 cases, the mosaic level in leucocyte DNA was slightly below the sensitivity threshold of Sanger sequencing; while in 3/5 cases, the allelic fraction was either very low (0.1-1%) or no mutations were detectable. The majority of mosaic mutations were located outside the somatic mutation cluster region of the gene.

Conclusions: The present data indicate a high prevalence of pathogenic mosaic APC mutations below the detection thresholds of routine diagnostics in adenomatous polyposis, even if high-coverage sequencing of leucocyte DNA alone is taken into account. This has important implications for both routine work-up and strategies to identify new causative genes in this patient group.
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http://dx.doi.org/10.1136/jmedgenet-2015-103468DOI Listing
March 2016
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