Personalized laboratory medicine: a patient-centered future approach

Žitnik, Irena Prodan; Černe, Darko; Mancini, Irene; Simi, Lisa; Pazzagli, Mario; Resta, Chiara Di; Podgornik, Helena; Lampret, Barbka Repič; Podkrajšek, Katarina Trebušak; Sipeky, Csilla; Schaik, Ron van; Brandslund, Ivan; Vermeersch, Pieter; Schwab, Matthias; Marc, Janja

doi:10.1515/cclm-2018-0181

Cited by 35 publications

(12 citation statements)

References 49 publications

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“…The HS phenotype may also be modified by co-occurrence with other disorders like glucose-6-phosphate dehydrogenase (G6PD) and Gilbert syndrome ( Aggarwal et al, 2019 ; Zou et al, 2020 ). Application of next-generation sequencing (NGS) has led to impressive progress in genetic disorder diagnostics, and it has provided unprecedented benefits for both personalized laboratory medicine and patients with rare genetic disorders ( Di Resta and Ferrari, 2018 ; Prodan Zitnik et al, 2018 ). NGS has promoted HS molecular diagnosis compared to clinical practice, including both targeted panel and whole exome sequencing (WES) ( Xue et al, 2019 ; Qin L. et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China

et al. 2020

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Hereditary spherocytosis (HS) is an inherited disorder characterized by anemia, splenomegaly, and spherical-shaped erythrocytes, caused by mutations in erythrocyte membrane Protein Genes ( ANK1 , SPTB , SLC4A1 , SPTA1 , and EPB42 ). We investigated molecular spectrum and genotype-phenotype correlation in HS patients in Hubei province, central China. Twenty-three patients with HS were included. A next-generation sequencing (NGS) panel targeting ANK1 , SPTB , SLC4A1 , SPTA1 , and EPB42 genes was used to screen potential variants. Sanger sequencing was applied to validate variants. Of the twenty-three patients, thirteen patients carried ANK1 variants, and ten patients harbored SPTB variants, including ten non-sense, six indel, four splice site, one start-loss, and one missense variant. Four out of twenty-two variants in our study were known, and eighteen variants were novel. Most ANK1 and SPTB variants were indel (5/12) or non-sense (7/10), respectively. Family member analysis in thirteen families showed that six variants were de novo . Variable expressivities were observed in a pair of twins with ANK1 c.341C > T variant, and two unrelated patients both carried ANK1 c.2T > A variant. Genotype-phenotype analysis found no significant difference between ANK1 and SPTB regarding the levels of Hb, RBC, MCV, MCH, and MCHC. However, variants in the ANK1 death domain were associated with lower levels of MCV and MCH compared to other ANK1 domains. In conclusion, NGS is a fast way to provide a molecular HS diagnosis. We also identified unique genetic and clinical characteristics of patients with HS in Hubei Province, China. However, a large sample size is needed to further investigate the genotype-phenotype correlation.

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Section: Introductionmentioning

confidence: 99%

Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China

et al. 2020

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“…The possible reason for this might be that the patients with FH in our study do not have any phenotypes characteristics to inflammation; consistent with the nature of FH, as it is a frequent disease (1/220-250) with a high variation in phenotypic expression associated with ASCVD ( Alhababi and Zayed, 2018 ; Perez-Calahorra et al, 2019 ). Also, in era of personalized medicine, it is significant to identify the possible targeted therapy using advanced omics technologies ( Prodan Žitnik et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Differentially Expressed Genes and Molecular Pathways in Familial Hypercholesterolemia Involved in Atherosclerosis: A Systematic and Bioinformatics Approach

Kumar

Bithia

et al. 2020

Front. Genet.

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Background and Aims: Familial hypercholesterolemia (FH) is one of the major risk factor for the progression of atherosclerosis and coronary artery disease. This study focused on identifying the dysregulated molecular pathways and core genes that are differentially regulated in FH and to identify the possible genetic factors and potential underlying mechanisms that increase the risk to atherosclerosis in patients with FH. Methods: The Affymetrix microarray dataset (GSE13985) from the GEO database and the GEO2R statistical tool were used to identify the differentially expressed genes (DEGs) from the white blood cells (WBCs) of five heterozygous FH patients and five healthy controls. The interaction between the DEGs was identified by applying the STRING tool and visualized using Cytoscape software. MCODE was used to determine the gene cluster in the interactive networks. The identified DEGs were subjected to the DAVID v6.8 webserver and ClueGo/CluePedia for functional annotation, such as gene ontology (GO) and enriched molecular pathway analysis of DEGs. Results: We investigated the top 250 significant DEGs ( p -value < 0.05; fold two change ≥ 1 or ≤ −1). The GO analysis of DEGs with significant differences revealed that they are involved in critical biological processes and molecular pathways, such as myeloid cell differentiation, peptidyl-lysine modification, signaling pathway of MyD88-dependent Toll-like receptor, and cell-cell adhesion. The analysis of enriched KEGG pathways revealed the association of the DEGs in ubiquitin-mediated proteolysis and cardiac muscle contraction. The genes involved in the molecular pathways were shown to be differentially regulated by either activating or inhibiting the genes that are essential for the canonical signaling pathways. Our study identified seven core genes ( UQCR11, UBE2N, ADD1, TLN1, IRAK3, LY96 , and MAP3K1 ) that are strongly linked to FH and lead to a higher risk of atherosclerosis. Conclusion: We identified seven core genes that represent potential molecular biomarkers for the diagnosis of atherosclerosis and might serve as a platform for developing therapeutics against both FH and atherosclerosis. However, functional studies are further needed to validate their role in the pathogenesis of FH and atherosclerosis.

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“…In addition, genetic testing provided an answer about the family history of the patient 2 and useful information when parents are planning for a new child. Therefore, genetic testing, especially next generation sequencing, is an established test method in clinical managements (40,41). Integrating genetic and clinical data enhances the care quality for the patients as well as their families (40)(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations

Nguyen

et al. 2020

Front. Pediatr.

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Background: Ornithine transcarbamylase deficiency (OTCD) is an X-linked recessive disorder and the most common error of the urea cycle, caused by the mutations in the OTC gene. Due to X-inactivation, 15-20% of female carriers present symptoms of OTCD at late onset. Early diagnosis of OTCD by molecular analysis in females is highly desirable. The aim of the study was to identify the mutations in two unrelated Vietnamese girls suspected with OTCD and the carriers in their families for definitive diagnosis and proper counseling. Case Presentation: Two patients presented with an acute encephalopathy at the first admission. Biochemical tests revealed hyperammonemia, hyperlactatemia, elevated glutamine level, elevated transaminase, elevated urinary orotic and uracil acid levels, and disorder of prothrombin time. Brain magnetic resonance imaging indicated cerebral edema. Based on the clinical and laboratory results, the two patients were diagnosed with urea cycle disorders. Therefore, the two patients were managed by stopping feeding, with infused glucose, l-carnitine, l-arginine, and sodium benzoate, and with hemofiltration. The two patients were alert and recovered with normal blood ammonia levels after 72 h of treatment. The family history of patient 1 showed that her brother died at 4 days of age due to a coma and dyspnea, while her parents were asymptomatic. Variable phenotypes were observed in three generations of the patient 2's family, including asymptomatic (mother), affected female adults dying at the first symptom (grandmother and aunt), and affected males dying in the first week of life (uncle, cousin, and siblings). Whole-exome sequencing showed two mutations in the OTC gene, including one novel missense mutation, c.365A>T, in the patient 1 and one previously reported splicing mutation, c.717+1G>A, in the patient 2. The two mutations are evaluated as likely pathogenic and pathogenic, respectively, according to the recommendations of the American College of Medical Genetics and Genomics (ACMG). Genetic analyses in the families indicated the mothers were heterozygous. Nguyen et al. Vietnamese Females With OTC Mutations Conclusion: Clinical, biochemical, and molecular findings accurately diagnosed the two patients with late-onset OTCD. Our results explained the genetic causes and proposed the risk in the patients' families, which could be useful for genetic counseling and monitoring in prenatal diagnosis.

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Personalized laboratory medicine: a patient-centered future approach

Cited by 35 publications

References 49 publications

Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China

Genetic and Clinical Characteristics of Patients With Hereditary Spherocytosis in Hubei Province of China

Analysis of Differentially Expressed Genes and Molecular Pathways in Familial Hypercholesterolemia Involved in Atherosclerosis: A Systematic and Bioinformatics Approach

Late-Onset Ornithine Transcarbamylase Deficiency and Variable Phenotypes in Vietnamese Females With OTC Mutations

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