The Application of Clinical Genetics最新文献

{"title":"Correlates of genetic attributions among parents of children in the USA with developmental disabilities.","authors":"Bridget Kiely,&nbsp;Sujit Vettam,&nbsp;Andrew Adesman","doi":"10.2147/TACG.S164757","DOIUrl":"https://doi.org/10.2147/TACG.S164757","url":null,"abstract":"<p><strong>Introduction: </strong>As technologies for identifying causal genetic variants in children with autism spectrum disorders (ASD) and other developmental conditions continue to advance, there is a need to understand the factors that influence parental beliefs about the causes of their child's disabilities. This study assessed the correlates of etiologic attributions among US parents of children with ASD, intellectual disability (ID), and/or developmental delay (DD).</p><p><strong>Methods: </strong>Data were obtained from the Centers for Disease Control and Prevention's nationally representative Survey of Pathways to Diagnosis and Services. Respondents were classified according to whether their child had ASD without ID or DD (ASD-only), ASD with ID and/or DD (ASD+ID/DD), or ID and/or DD without ASD (ID/DD-only). Respondents rated the extent to which they believed that genetics/heredity and environmental exposures (prenatal and/or postnatal) had contributed to their child's condition. Logistic regression analyses and chi-square tests were used to assess the relationship between parental beliefs and child characteristics.</p><p><strong>Results: </strong>The parents of children with comorbid ASD and ID/DD were found to be significantly less likely than those in the other condition groups to attribute their child's condition to genetics. Within the ASD+ID/DD group, parental endorsement of genetics was lower among those who reported a history of language regression (<i>p</i>=0.006).</p><p><strong>Conclusion: </strong>Further research is needed to evaluate the impact of parental genetic attributions on medical decision-making.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"55-61"},"PeriodicalIF":3.1,"publicationDate":"2019-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S164757","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37202284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MTHFR C677T polymorphism and risk of nonsyndromic cleft lip with or without cleft palate in the Moroccan population.","authors":"Amine Rafik,&nbsp;Laila Rachad,&nbsp;Abdou-Samad Kone,&nbsp;Sellama Nadifi","doi":"10.2147/TACG.S194166","DOIUrl":"https://doi.org/10.2147/TACG.S194166","url":null,"abstract":"<p><strong>Background: </strong>Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common craniofacial malformations observed. Several studies suggest that the decrease in folate has been associated with a higher risk of NSCL/P. The present study aimed to determine the association of 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism gene with the occurrence of NSCL/P in the Moroccan population.</p><p><strong>Methods: </strong>MTHFR C677T was genotyped in 52 Moroccan patients and 182 unrelated controls, using a PCR followed by restriction fragment length polymorphism.</p><p><strong>Results: </strong>The results of the study revealed a genotypic and phenotypic distribution in equilibrium with Hardy-Weinberg's law (χ²=0.36, <i>P</i>=0.55). The frequency of heterozygous genotype C/T and the T allele in controls and patients were 40.7% vs 15.4% and 26%, respectively.</p><p><strong>Conclusion: </strong>A low association was found between the C677T polymorphism of the MTHFR gene and a risk for the development of NSCL/P in the Moroccan population (OR =0.24, <i>P</i>=0.0005).</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"51-54"},"PeriodicalIF":3.1,"publicationDate":"2019-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S194166","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37064403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multiple phenotypic domains of Fabry disease and their relevance for establishing genotype- phenotype correlations.","authors":"João Paulo Oliveira,&nbsp;Susana Ferreira","doi":"10.2147/TACG.S146022","DOIUrl":"https://doi.org/10.2147/TACG.S146022","url":null,"abstract":"<p><p>Fabry disease (FD) is a rare X-linked glycosphingolipidosis resulting from deficient α-galactosidase A (AGAL) activity, caused by pathogenic mutations in the <i>GLA</i> gene. In males, the multisystemic involvement and the severity of tissue injury are critically dependent on the level of AGAL residual enzyme activity (REA) and on the metabolic load of the disease, but organ susceptibility to damage varies widely, with heart appearing as the most vulnerable to storage pathology, even with relatively high REA. The expression of FD can be conceived as a multidomain phenotype, where each of the component domains is the laboratory or clinical expression of the causative <i>GLA</i> mutation along a complex pathophysiologic cascade pathway. The AGAL enzyme activity is the most clinically useful marker of the protein phenotype. The metabolic phenotype and the pathologic phenotype are diverse expressions of the storage pathology, respectively, assessed by biochemical and histological/ultrastructural methods. The storage phenotypes are the direct consequences of enzyme deficiency and hence, together with the enzymatic phenotype, constitute the more specific diagnostic markers of FD. In the pathophysiology cascade, the clinical phenotypes are most distantly linked to the underlying genetic causation, being critically influenced by the patients' gender and age, and modulated by the effects of variation in other genetic loci, of polygenic inheritance and of environmental risk factors. A major challenge in the clinical phenotyping of patients with FD is the differential diagnosis between its nonspecific, later-onset complications, particularly the cerebrovascular, cardiac and renal, and similar chronic illnesses that are common in the general population. Comprehensive phenotyping, whenever possible performed in hemizygous males, is therefore crucial for grading the severity of pathogenic <i>GLA</i> variants, to clarify the phenotypic correlations of hypomorphic alleles, to define benign polymorphisms, as well as to establish the pathogenicity of variants of uncertain significance.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"35-50"},"PeriodicalIF":3.1,"publicationDate":"2019-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S146022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37064404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"c.259A>C in the fibrinogen gene of alpha chain (<i>FGA</i>) is a fibrinogen with thrombotic phenotype.","authors":"Ophira Salomon,&nbsp;Ortal Barel,&nbsp;Eran Eyal,&nbsp;Reut Shnerb Ganor,&nbsp;Yeroham Kleinbaum,&nbsp;Mordechai Shohat","doi":"10.2147/TACG.S190599","DOIUrl":"https://doi.org/10.2147/TACG.S190599","url":null,"abstract":"<p><strong>Introduction: </strong>Dysfibrinogenemia is a rare inherited disease that results from mutation in one of the three fibrinogen genes. Diagnosis can be misleading since it may present as a bleeding tendency or thrombosis and a specific coagulation test for diagnosis is not routinely available.</p><p><strong>Aim: </strong>To search for a new candidate gene of thrombophilia in a family with three generations of arterial and venous thrombosis.</p><p><strong>Methods: </strong>Whole exome sequencing followed by Sanger validation and segregation analysis was carried out. In addition, structural modeling was performed. Screening for thrombophilia along with blood counts, prothrombin time, activated partial thromboplastin, thrombin, reptilase time, and fibrinogen was done in each patient.</p><p><strong>Results and discussion: </strong>A missense c.259A>C, p.K87Q (g.chr4: 155510050A-C) (rs764281241) in <i>FGA</i> gene was found in all three siblings without any other known thrombophilia marker to explain thrombosis in all three siblings. It is expected to be damaging by six out of seven prediction programs and is very rare in the entire population with Exac=0.000008.</p><p><strong>Conclusion: </strong>The occurrence of the c.259A>C mutation in <i>FGA</i> may well explain the thrombosis phenotype of the affected family and is suggested as a new marker for thrombophilia phenotype.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"27-33"},"PeriodicalIF":3.1,"publicationDate":"2019-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S190599","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37064402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two novel variants in the <i>TCF12</i> gene identified in cases with craniosynostosis.","authors":"Athanasios Goumenos,&nbsp;Eirini Tsoutsou,&nbsp;Joanne Traeger-Synodinos,&nbsp;Dimitrios Petychakis,&nbsp;Maria Gavra,&nbsp;Aggeliki Kolialexi,&nbsp;Helena Frysira","doi":"10.2147/TACG.S190855","DOIUrl":"https://doi.org/10.2147/TACG.S190855","url":null,"abstract":"<p><p>Craniosynostosis (CS) is a condition where one or more of the cranial sutures fuse prematurely. It affects almost 1/2,000 newborns, and includes both syndromic and non-syndromic cases. To date, variants in over 70 different genes have been associated with the expression of CS. In this report, we describe two unrelated cases that presented with coronal CS. <i>TCF12</i> sequencing analysis revealed novel frameshift nucleotide variants, which were evaluated as pathogenic according to the current guidelines for interpreting sequence variants. These findings expand the spectrum of <i>TCF12</i> gene variants related with CS and support the importance of screening for such variants in patients with coronal synostosis.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"19-25"},"PeriodicalIF":3.1,"publicationDate":"2019-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S190855","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37045607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics of COPA syndrome.","authors":"Rajni Kumrah,&nbsp;Babu Mathew,&nbsp;Pandiarajan Vignesh,&nbsp;Surjit Singh,&nbsp;Amit Rawat","doi":"10.2147/TACG.S153600","DOIUrl":"https://doi.org/10.2147/TACG.S153600","url":null,"abstract":"<p><p>Inborn errors of immunity usually not only result in immunodeficiency but may also manifest as immune dysregulation in the form of autoinflammation, autoimmunity, or sometimes malignancy. One of the most recently discovered monogenic disorder of immune dysregulation is COPA syndrome. COPA syndrome is an inherited autoimmune disorder caused by mutations in <i>COPA</i> gene. <i>COPA</i> gene encodes for α subunit of the COP1 protein, which is involved in the reverse vesicular protein transport from Golgi apparatus to the endoplasmic reticulum (ER). The inheritance pattern of COPA syndrome is autosomal dominant, and the patients typically present with interstitial lung disease with pulmonary hemorrhage and subsequently develop arthritis. Immunological features involve autoantibody formation, elevated expression of IL-1β and IL-6, and increase in the number of Th17 cells. Molecular pathophysiology of COPA syndrome is not clearly understood. However, it is known that accumulation of unfolded proteins in ER leads to ER stress, which is an indirect result of aberrant vesicular transport of proteins from Golgi apparatus to ER and defective cellular autophagy. ER stress induces inflammation and is responsible for pathogenesis of a large number of chronic inflammatory diseases. Unfolded protein response process responds to improperly folded proteins and defends against stress in ER to ensure the fidelity of the protein folding. It maintains the expression of stress-response genes and causes initiation of inflammatory signaling pathways essential for the innate immunity. Mutation in <i>COPA</i> gene associated with defective protein sorting to ER has unearthed a new primary immunodeficiency disease with a unique clinical phenotype. This review highlights the clinical and molecular aspects of COPA syndrome.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"11-18"},"PeriodicalIF":3.1,"publicationDate":"2019-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S153600","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36998615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A two gene-based risk score predicts alcoholic cirrhosis development in males with at-risk alcohol consumption.","authors":"Rosellina Margherita Mancina,&nbsp;Flaminia Ferri,&nbsp;Alessio Farcomeni,&nbsp;Antonio Molinaro,&nbsp;Angela Maffongelli,&nbsp;Monica Mischitelli,&nbsp;Edoardo Poli,&nbsp;Lucia Parlati,&nbsp;Maria Antonella Burza,&nbsp;Adriano De Santis,&nbsp;Fabio Attilia,&nbsp;Claudia Rotondo,&nbsp;Maria Margherita Rando,&nbsp;Maria Luisa Attilia,&nbsp;Mauro Ceccanti,&nbsp;Stefano Ginanni Corradini","doi":"10.2147/TACG.S187922","DOIUrl":"https://doi.org/10.2147/TACG.S187922","url":null,"abstract":"<p><strong>Background: </strong>Alcoholic cirrhosis represents 1% of all cause-of-deaths worldwide. Its incidence is higher in males and results from the combination of environmental and genetic factors. Among all the genetic determinants of alcoholic cirrhosis, the patatin-like phospholipase domain protein 3 (<i>PNPLA3</i>) rs738409 represents the most widely validated determinant. Recent cross-sectional studies on alcohol abusers identified transmembrane-6 superfamily member 2 (<i>TM6SF2</i>) rs58542926, membrane bound O-acyltransferase domain containing 7 (<i>MBOAT7</i>) rs641738, and cluster of differentiation 14 (<i>CD14</i>) rs2569190 as new genetic risk factors for alcoholic cirrhosis. We aimed to develop a gene-based risk score to predict the incidence of alcoholic cirrhosis in males with at-risk alcohol consumption.</p><p><strong>Materials and methods: </strong>A total of 416 male at-risk alcohol drinkers were retrospectively examined. The association between alcoholic cirrhosis incidence and <i>PNPLA3</i>, <i>CD14</i>, <i>TM6SF2</i>, and <i>MBOAT7</i> variants was tested. Age at onset of at-risk alcohol consumption, age, and body mass index (BMI) were included as covariates to determine the prediction score for alcoholic cirrhosis incidence by evaluating time-dependent receiver operating characteristic curves.</p><p><strong>Results: </strong>We found that <i>PNPLA3</i>, <i>CD14</i>, and <i>TM6SF2</i> were associated with alcoholic cirrhosis prevalence. <i>PNPLA3</i> and <i>CD14</i> were also associated with its incidence. The best predictive score formula was (age at onset of at-risk alcohol consumption × 0.1) + (number of <i>CD14</i> allele T) + (number of <i>PNPLA3</i> allele M) + (BMI × 0.1). A threshold of 7.27 was identified as cutoff for the predictive risk of alcoholic cirrhosis development in 36 years from the onset of at-risk alcohol consumption with 70.1% sensitivity and 78.7% specificity.</p><p><strong>Conclusion: </strong>We developed the first score for alcoholic cirrhosis prediction that combines clinical and genetic factors.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"12 ","pages":"1-10"},"PeriodicalIF":3.1,"publicationDate":"2019-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S187922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36927642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adult-onset type II citrullinemia: Current insights and therapy.","authors":"Kiyoshi Hayasaka,&nbsp;Chikahiko Numakura","doi":"10.2147/TACG.S162084","DOIUrl":"https://doi.org/10.2147/TACG.S162084","url":null,"abstract":"<p><p>Citrin deficiency is a recessively inherited metabolic disorder with age-dependent clinical manifestations. It causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Patients with NICCD present with intrahepatic cholestasis in the neonatal period and usually respond to the treatment with medium-chain triglyceride (MCT) supplement and lactose-restricted formula. In adulthood, CTLN2 develops in <10 % of the patients showing hyperammonemic encephalopathy. Patients with CTLN2 required liver transplantation for the most promising prognosis; however, they were successfully treated with MCT supplement with a low carbohydrate formula. Citrin deficiency is caused by mutations in <i>SLC25A13</i> on chromosome 7q21.3, with a high frequency in East Asia, including Japan. Citrin is aspartate/glutamate transporter in mitochondria, a component of malate-aspartate nicotinamide adenine dinucleotide hydrogen shuttle, and is essential for the hepatic glycolysis. Although the precise pathophysiology of citrin deficiency remains unclear, recent reports for the effective MCT supplement therapy and downregulation of peroxisome proliferator-activated receptor α suggest that citrin deficiency impairs hepatic de novo lipogenesis coupled with glycolysis leading to the energy deficit of hepatocytes. Herein, we review the current therapeutic and pathological understanding of CTLN2.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"11 ","pages":"163-170"},"PeriodicalIF":3.1,"publicationDate":"2018-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S162084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36859292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel de novo <i>TBX5</i> mutation in a patient with Holt-Oram syndrome.","authors":"Lady J Ríos-Serna,&nbsp;Lorena Díaz-Ordoñez,&nbsp;Estephania Candelo,&nbsp;Harry Pachajoa","doi":"10.2147/TACG.S183418","DOIUrl":"https://doi.org/10.2147/TACG.S183418","url":null,"abstract":"<p><p>Holt-Oram syndrome (HOS) is an autosomal dominant disorder characterized by congenital cardiac defects and congenital deformities of the upper limbs. Herein, we report the case of a 2-year-old patient presenting with clinical diagnostic criteria of HOS with interatrial and interventricular communication associated with hip dysplasia and upper limb reduction composed of radial ray anomaly. A novel de novo, potentially pathogenic variant in the <i>TBX5</i> gene at NM_181486.2:c.243-1G>C was identified.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"11 ","pages":"157-162"},"PeriodicalIF":3.1,"publicationDate":"2018-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S183418","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36816144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel <i>ATP7A</i> gene mutation in a patient with Menkes disease.","authors":"Gabriela Caicedo-Herrera,&nbsp;Estephania Candelo,&nbsp;Juan Pinilla,&nbsp;Andrés Vidal,&nbsp;Santiago Cruz,&nbsp;Harry Mauricio Pachajoa","doi":"10.2147/TACG.S180087","DOIUrl":"https://doi.org/10.2147/TACG.S180087","url":null,"abstract":"<p><strong>Background: </strong>Menkes disease is a congenital neurodegenerative disorder caused by <i>ATP7A</i> gene mutations. Clinical features include epilepsy, growth delay, reduced muscle strength, skin laxity, abnormal hair, and urologic abnormalities.</p><p><strong>Case presentation: </strong>We describe an infant with developmental delay, neurologic degeneration, and kinky hair. Molecular test revealed a novel heterozygous mutation in exon 21 of the <i>ATP7A</i> gene. The genotype and phenotype of the patient were compared with those of the patients reported in the literature.</p><p><strong>Conclusion: </strong>We propose that this mutation caused a dysfunctional protein resulting in classical Menkes disease. This case adds to the spectrum of pathogenic variants of the <i>ATP7A</i> gene known to cause disease.</p>","PeriodicalId":506374,"journal":{"name":"The Application of Clinical Genetics","volume":"11 ","pages":"151-155"},"PeriodicalIF":3.1,"publicationDate":"2018-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.2147/TACG.S180087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36816143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}