Raymond Kim - Academia.edu (original) (raw)

Papers by Raymond Kim

Database

Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individua... more Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individuals to developing tumors in many organs. There is significant phenotypic variability and genetic variants encountered within this syndrome, posing a considerable challenge to patient care. The lack of VHL variant data sharing paired with the absence of aggregated genotype–phenotype information results in an arduous process, when characterizing genetic variants and predicting patient prognosis. To address these gaps in knowledge, the Clinical Genome Resource (ClinGen) VHL Variant Curation Expert Panel (VCEP) has been resolving a list of variants of uncertain significance within the VHL gene. Through community curation, we crowdsourced the laborious task of variant annotation by modifying the ClinGen Community Curation (C3)-developed Baseline Annotation protocol and annotating all published VHL cases with the reported genotype–phenotype information in Hypothes.is, an open-access web annotat...

Human Genetics

Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current c... more Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page—supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient i...

Journal of Clinical Medicine

Statins have been shown to reduce myocardial infarction (MI) in cardiac and vascular surgery. MI ... more Statins have been shown to reduce myocardial infarction (MI) in cardiac and vascular surgery. MI is common in hip fracture. This study aims to investigate whether statins decrease MI in hip fracture surgery and reduce mortality resulting from MI. Patients aged 65 years and above with a low-energy hip fracture were identified between January 2015 and December 2017. Demographics, comorbidities, predictive scores, medications and outcomes were assessed retrospectively. The primary outcome was inpatient MI. The secondary outcome was inpatient mortality resulting from MI, for which fatal and non-fatal MI were modelled. Regression analysis was conducted with propensity score weighting. Hip fracture occurred in 1166 patients, of which 391 (34%) were actively taking statins. Thirty-one (2.7%) patients were clinically diagnosed with MI. They had a higher inpatient mortality than those who did not sustain an MI (35% vs. 5.3%, p < 0.0001). No reduction was seen between statin use and the oc...

BMC Medical Genomics

Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typi... more Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1. Case presentation A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stab...

npj Genomic Medicine, 2022

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the... more Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95–100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10–55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL var...

The Spectrum of Neuroendocrine Neoplasia, 2020

Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often... more Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often present with subtle clinical or biochemical features. The well-recognized entities include a spectrum of associated neoplasms harboring various degrees of biologic aggressiveness, which often show variable degrees of genotype-phenotype correlations and penetrance. The rate of germline susceptibility in endocrine neoplasms is generally underestimated as most healthcare providers do not routinely consider the possibility of germline disease in a seemingly sporadic presentation in adults over the age of 50–60 years. Variations in disease penetrance and de novo pathogenic variants can lead to late-onset manifestations of inherited NENs that can simulate sporadic disease in the absence of family history. Some of these also manifest with a non-syndromic presentation as seen in patients with familial isolated hyperparathyroidism (FIHP), familial isolated pituitary adenoma (FIPA), as well as in a subset of multiple endocrine neoplasia type 2 (MEN2) patients manifesting only with medullary thyroid carcinoma (formerly known as familial isolated medullary thyroid carcinoma syndrome). The suspicion of an underlying germline susceptibility for NENs should be based on tumor multifocality and morphology including non-tumorous parenchyma, identification of hyperplasia-to-neoplasia progression sequence, early-onset, and coexistence of synchronous or asynchronous endocrinopathies, including endocrine neoplasias. The delivery of genetic care for hereditary inherited disorders is multifaceted and involves multiple healthcare practitioners, including laboratory geneticists, physician geneticists, and genetic counsellors.

Additional file 1. Supplementary Materials, contains supplemental figures and tables outlining cu... more Additional file 1. Supplementary Materials, contains supplemental figures and tables outlining curation SOP guidelines illustrated by workflow figures, tables, and screenshots from the CIViC interface.

Additional file 3: Participant contact letter template.

Monte Carlo methods are a class of numerical algorithms that depend on repeated samples of random... more Monte Carlo methods are a class of numerical algorithms that depend on repeated samples of random variables to obtain results; the numerical solution to the problem at hand can converge to the analytical solution by increasing the number of samples. However, as the problem becomes more complex, this procedure of reaching an accepted solution becomes inefficient: the problem may require higher orders of samples to achieve a single order of accuracy. Thus, variance reduction techniques exist to alter our method of performing the Monte Carlo method to achieve a faster convergence rate and a more accurate approximation given the same number of samples. In this paper we evaluate several variance reduction techniques of the Monte Carlo method and its application in the global illumination problem in computer graphics.

Additional file 7: Table S2. Returnable variant details.

Additional file 2: Research interpretation report template.

is online at: Circulation Information about subscribing to Subscriptions:

Information about reprints can be found online at: Reprints: document. Permissions and Rights Que... more Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer this process is available in the click Request Permissions in the middle column of the Web page under Services. Further information about Office. Once the online version of the published article for which permission is being requested is located, can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions: by guest on February 26,

International Journal of Molecular Sciences, 2020

Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chro... more Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chronic neurocognitive deficits. Little is known about the molecular pathways that contribute to persistent concussion symptoms. We hypothesized that salivary measurement of microribonucleic acids (miRNAs), a class of epitranscriptional molecules implicated in concussion pathophysiology, would provide insights about the molecular cascade resulting from recurrent concussions. This hypothesis was tested in a case-control study involving 13 former professional football athletes with a history of recurrent concussion, and 18 age/sex-matched peers. Molecules of interest were further validated in a cross-sectional study of 310 younger individuals with a history of no concussion (n = 230), a single concussion (n = 56), or recurrent concussions (n = 24). There was no difference in neurocognitive performance between the former professional athletes and their peers, or among younger individuals with v...

Medicina, 2021

Background and Objectives: An increasing global burden of geriatric hip fractures is anticipated.... more Background and Objectives: An increasing global burden of geriatric hip fractures is anticipated. The appropriate treatment for fractures is of ongoing interest and becoming more relevant with an aging population and finite health resources. Trochanteric fractures constitute approximately half of all hip fractures with the medial calcar critical to fracture stability. In the management of unstable trochanteric fractures, it is assumed that intramedullary nails and longer implants will lead to less failure. However, the lack of power, inclusion of older generation femoral nails, and a variable definition of stability complicate interpretation of the literature. Materials and Methods: Between January 2012 and December 2017, a retrospective analysis of operatively treated geriatric trochanteric hip fracture patients were examined at a Level 1 Trauma Centre. The treatment was with a long and short version of one type of trochanteric nail. Unstable trochanteric fractures with medial calc...

Current Oncology, 2021

This study compares knowledge, experience and understanding of genetic testing, and psychological... more This study compares knowledge, experience and understanding of genetic testing, and psychological outcomes among breast and ovarian cancer patients undergoing multi-gene panel testing via genetic counselor-mediated (GMT) or oncologist-mediated (OMT) testing models. A pragmatic, prospective survey of breast and ovarian cancer patients pursuing genetic testing between January 2017 and August 2019 was conducted at the Princess Margaret Cancer Centre in Toronto, Canada. A total of 120 (80 GMT; 40 OMT) individuals completed a survey administered one week following consent to genetic testing. Compared to OMT, the GMT cohort had higher median knowledge (8 vs. 9; p = 0.025) and experience/understanding scores (8.5 vs. 10; p < 0.001) at the time of genetic testing. Significant differences were noted in the potential psychological concerns experienced, with individuals in the GMT cohort more likely to screen positive in the hereditary predisposition domain of the Psychosocial Aspects of He...

Chronic rhinosinusitis (CRS) and bronchiectasis are alike in features of chronic mucosal inflamma... more Chronic rhinosinusitis (CRS) and bronchiectasis are alike in features of chronic mucosal inflammation and excess mucus output. While a spectrum of lower airway dysfunctions may be seen with CRS, concurrent bronchiectasis and CRS lead to more frequent lower airway exacerbations and a significant reduction in quality of life. While the concept of unified airway disease may explain this coexistence, there remains no clear link of causality. Surgical optimization of the upper airway has demonstrated significant improvement in both quality of life and pulmonary function in patients with asthma and cystic fibrosis. However, in patients with bronchiectasis, the irreversible nature of structural damage appears to limit pulmonary function improvement, although it has shown to improve quality of life and reduce the frequency of pulmonary exacerbations.

Database

Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individua... more Von Hippel–Lindau (VHL) disease is a rare, autosomal dominant disorder that predisposes individuals to developing tumors in many organs. There is significant phenotypic variability and genetic variants encountered within this syndrome, posing a considerable challenge to patient care. The lack of VHL variant data sharing paired with the absence of aggregated genotype–phenotype information results in an arduous process, when characterizing genetic variants and predicting patient prognosis. To address these gaps in knowledge, the Clinical Genome Resource (ClinGen) VHL Variant Curation Expert Panel (VCEP) has been resolving a list of variants of uncertain significance within the VHL gene. Through community curation, we crowdsourced the laborious task of variant annotation by modifying the ClinGen Community Curation (C3)-developed Baseline Annotation protocol and annotating all published VHL cases with the reported genotype–phenotype information in Hypothes.is, an open-access web annotat...

Human Genetics

Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current c... more Copy number variants (CNVs) represent major etiologic factors in rare genetic diseases. Current clinical CNV interpretation workflows require extensive back-and-forth with multiple tools and databases. This increases complexity and time burden, potentially resulting in missed genetic diagnoses. We present the Suite for CNV Interpretation and Prioritization (SCIP), a software package for the clinical interpretation of CNVs detected by whole-genome sequencing (WGS). The SCIP Visualization Module near-instantaneously displays all information necessary for CNV interpretation (variant quality, population frequency, inheritance pattern, and clinical relevance) on a single page—supported by modules providing variant filtration and prioritization. SCIP was comprehensively evaluated using WGS data from 1027 families with congenital cardiac disease and/or autism spectrum disorder, containing 187 pathogenic or likely pathogenic (P/LP) CNVs identified in previous curations. SCIP was efficient i...

Journal of Clinical Medicine

Statins have been shown to reduce myocardial infarction (MI) in cardiac and vascular surgery. MI ... more Statins have been shown to reduce myocardial infarction (MI) in cardiac and vascular surgery. MI is common in hip fracture. This study aims to investigate whether statins decrease MI in hip fracture surgery and reduce mortality resulting from MI. Patients aged 65 years and above with a low-energy hip fracture were identified between January 2015 and December 2017. Demographics, comorbidities, predictive scores, medications and outcomes were assessed retrospectively. The primary outcome was inpatient MI. The secondary outcome was inpatient mortality resulting from MI, for which fatal and non-fatal MI were modelled. Regression analysis was conducted with propensity score weighting. Hip fracture occurred in 1166 patients, of which 391 (34%) were actively taking statins. Thirty-one (2.7%) patients were clinically diagnosed with MI. They had a higher inpatient mortality than those who did not sustain an MI (35% vs. 5.3%, p < 0.0001). No reduction was seen between statin use and the oc...

BMC Medical Genomics

Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typi... more Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1. Case presentation A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stab...

npj Genomic Medicine, 2022

Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the... more Von Hippel-Lindau disease (VHL) is an autosomal dominant, inherited syndrome with variants in the VHL gene causing predisposition to multi-organ benign and malignant neoplasms. A germline VHL variant is identified in 95–100% of individuals with a clinical diagnosis of VHL. Here, we present the case of an individual with a clinical diagnosis of VHL disease where peripheral blood DNA analysis did not detect a VHL variant. Sequencing of four tumor tissues (ccRCC, pheochromocytoma, lung via sputum, liver) revealed a VHL c.593 T > C (p.Leu198Pro) variant at varying allele fractions (range: 10–55%) in all tissues. Re-examination of the peripheral blood sequencing data identified this variant at 6% allele fraction. Tumor analysis revealed characteristic cytomorphological, immunohistochemical reactivity for alpha-inhibin, and CAIX, and reduced pVHL reactivity supported VHL-related pseudohypoxia. This report of a rare case of VHL mosaicism highlights the value of tissue testing in VHL var...

The Spectrum of Neuroendocrine Neoplasia, 2020

Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often... more Inherited neuroendocrine neoplasms (NENs) represent a heterogeneous group of disorders that often present with subtle clinical or biochemical features. The well-recognized entities include a spectrum of associated neoplasms harboring various degrees of biologic aggressiveness, which often show variable degrees of genotype-phenotype correlations and penetrance. The rate of germline susceptibility in endocrine neoplasms is generally underestimated as most healthcare providers do not routinely consider the possibility of germline disease in a seemingly sporadic presentation in adults over the age of 50–60 years. Variations in disease penetrance and de novo pathogenic variants can lead to late-onset manifestations of inherited NENs that can simulate sporadic disease in the absence of family history. Some of these also manifest with a non-syndromic presentation as seen in patients with familial isolated hyperparathyroidism (FIHP), familial isolated pituitary adenoma (FIPA), as well as in a subset of multiple endocrine neoplasia type 2 (MEN2) patients manifesting only with medullary thyroid carcinoma (formerly known as familial isolated medullary thyroid carcinoma syndrome). The suspicion of an underlying germline susceptibility for NENs should be based on tumor multifocality and morphology including non-tumorous parenchyma, identification of hyperplasia-to-neoplasia progression sequence, early-onset, and coexistence of synchronous or asynchronous endocrinopathies, including endocrine neoplasias. The delivery of genetic care for hereditary inherited disorders is multifaceted and involves multiple healthcare practitioners, including laboratory geneticists, physician geneticists, and genetic counsellors.

Additional file 1. Supplementary Materials, contains supplemental figures and tables outlining cu... more Additional file 1. Supplementary Materials, contains supplemental figures and tables outlining curation SOP guidelines illustrated by workflow figures, tables, and screenshots from the CIViC interface.

Additional file 3: Participant contact letter template.

Monte Carlo methods are a class of numerical algorithms that depend on repeated samples of random... more Monte Carlo methods are a class of numerical algorithms that depend on repeated samples of random variables to obtain results; the numerical solution to the problem at hand can converge to the analytical solution by increasing the number of samples. However, as the problem becomes more complex, this procedure of reaching an accepted solution becomes inefficient: the problem may require higher orders of samples to achieve a single order of accuracy. Thus, variance reduction techniques exist to alter our method of performing the Monte Carlo method to achieve a faster convergence rate and a more accurate approximation given the same number of samples. In this paper we evaluate several variance reduction techniques of the Monte Carlo method and its application in the global illumination problem in computer graphics.

Additional file 7: Table S2. Returnable variant details.

Additional file 2: Research interpretation report template.

is online at: Circulation Information about subscribing to Subscriptions:

Information about reprints can be found online at: Reprints: document. Permissions and Rights Que... more Information about reprints can be found online at: Reprints: document. Permissions and Rights Question and Answer this process is available in the click Request Permissions in the middle column of the Web page under Services. Further information about Office. Once the online version of the published article for which permission is being requested is located, can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions: by guest on February 26,

International Journal of Molecular Sciences, 2020

Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chro... more Recurrent concussions increase risk for persistent post-concussion symptoms, and may lead to chronic neurocognitive deficits. Little is known about the molecular pathways that contribute to persistent concussion symptoms. We hypothesized that salivary measurement of microribonucleic acids (miRNAs), a class of epitranscriptional molecules implicated in concussion pathophysiology, would provide insights about the molecular cascade resulting from recurrent concussions. This hypothesis was tested in a case-control study involving 13 former professional football athletes with a history of recurrent concussion, and 18 age/sex-matched peers. Molecules of interest were further validated in a cross-sectional study of 310 younger individuals with a history of no concussion (n = 230), a single concussion (n = 56), or recurrent concussions (n = 24). There was no difference in neurocognitive performance between the former professional athletes and their peers, or among younger individuals with v...

Medicina, 2021

Background and Objectives: An increasing global burden of geriatric hip fractures is anticipated.... more Background and Objectives: An increasing global burden of geriatric hip fractures is anticipated. The appropriate treatment for fractures is of ongoing interest and becoming more relevant with an aging population and finite health resources. Trochanteric fractures constitute approximately half of all hip fractures with the medial calcar critical to fracture stability. In the management of unstable trochanteric fractures, it is assumed that intramedullary nails and longer implants will lead to less failure. However, the lack of power, inclusion of older generation femoral nails, and a variable definition of stability complicate interpretation of the literature. Materials and Methods: Between January 2012 and December 2017, a retrospective analysis of operatively treated geriatric trochanteric hip fracture patients were examined at a Level 1 Trauma Centre. The treatment was with a long and short version of one type of trochanteric nail. Unstable trochanteric fractures with medial calc...

Current Oncology, 2021

This study compares knowledge, experience and understanding of genetic testing, and psychological... more This study compares knowledge, experience and understanding of genetic testing, and psychological outcomes among breast and ovarian cancer patients undergoing multi-gene panel testing via genetic counselor-mediated (GMT) or oncologist-mediated (OMT) testing models. A pragmatic, prospective survey of breast and ovarian cancer patients pursuing genetic testing between January 2017 and August 2019 was conducted at the Princess Margaret Cancer Centre in Toronto, Canada. A total of 120 (80 GMT; 40 OMT) individuals completed a survey administered one week following consent to genetic testing. Compared to OMT, the GMT cohort had higher median knowledge (8 vs. 9; p = 0.025) and experience/understanding scores (8.5 vs. 10; p < 0.001) at the time of genetic testing. Significant differences were noted in the potential psychological concerns experienced, with individuals in the GMT cohort more likely to screen positive in the hereditary predisposition domain of the Psychosocial Aspects of He...

Chronic rhinosinusitis (CRS) and bronchiectasis are alike in features of chronic mucosal inflamma... more Chronic rhinosinusitis (CRS) and bronchiectasis are alike in features of chronic mucosal inflammation and excess mucus output. While a spectrum of lower airway dysfunctions may be seen with CRS, concurrent bronchiectasis and CRS lead to more frequent lower airway exacerbations and a significant reduction in quality of life. While the concept of unified airway disease may explain this coexistence, there remains no clear link of causality. Surgical optimization of the upper airway has demonstrated significant improvement in both quality of life and pulmonary function in patients with asthma and cystic fibrosis. However, in patients with bronchiectasis, the irreversible nature of structural damage appears to limit pulmonary function improvement, although it has shown to improve quality of life and reduce the frequency of pulmonary exacerbations.