Application of Clinical Genetics最新文献

Background: Congenital sucrase isomaltase deficiency (CSID) is in general a very rare disease. However, 2-3% of the Greenlandic population are homozygous (HO) carriers of an Arctic-specific loss-of-function (LoF) variant in the sucrase-isomaltase (SI) encoding gene, causing CSID. The condition is characterized by gastrointestinal symptoms such as stomachache, diarrhea, and weight loss when consuming sucrose, the most common dietary sugar. However, the awareness of the condition in the population and the healthcare system seems to be limited, potentially leading to a higher healthcare burden. Hence, we aimed to investigate whether HO-carriers visit the healthcare system more with gastrointestinal symptoms compared to the control groups by using registry data.

Methods: We performed a case-control study identifying cases and controls using genotype information from the 1999-2001 and 2005-2010 Greenlandic health population cohorts. The cases were defined as HO LoF SI-carriers and controls were defined as non-carriers and were matched (1:1) on sex, age, place of residence, and European genetic admixture. We used electronic medical records to assess the number of electronic medical record contacts (EMRc) related to gastrointestinal symptoms and the number of gastrointestinal-related diagnostic procedures.

Results: A total of 80 HO-carriers and 80 non-carriers were included. The HO-carriers had 19% more EMRc related to gastrointestinal symptoms (IRR, 1.19, 95% CI [1.02;1.40], p=0.02) and had a 41% higher incidence of gastrointestinal related diagnostic procedures compared to controls (IRR, 1.41, 95% CI [1.05-1.92], p=0.02). Only one HO-carrier was aware of the condition according to the electronic medical records.

Conclusion: HO-carriers of the LoF SI-variant had both significantly more gastrointestinal-related EMRc and significantly more diagnostic procedures conducted due to gastrointestinal symptoms. Only one HO-carrier was aware of the condition. Given the high prevalence of HO-carriers in the Greenlandic population, we anticipate that diagnosing more patients with CSID and providing dietary advice could potentially reduce symptom burden and healthcare visits among HO-carriers.

Introduction: Sudden cardiac death (SCD) is a serious threat. In individuals under the age of 35 years sudden arrhythmic death is the most frequent cause. In younger persons, genetically determined cardiac diseases (eg, cardiomyopathies and ion-channel diseases) account for an important proportion of these cases.

Methods: We investigated the case of a 23-year-old male with SCD, specific ECG changes and left ventricular hypertrophy. Family history was significant for SCD in the paternal line. A precise analysis was performed by an international multidisciplinary expert panel including autopsy of the index patient's heart, molecular autopsy, whole-exome sequencing, analysis of the pedigree and examination of available family members.

Results: Three cases of SCD were reported in paternal relatives. The index patient exhibited specific ECG changes (ST-depression), which were also found in five paternal relatives and the brother of the index patient. Post-mortem analysis of the heart yielded mild idiopathic concentric hypertrophy without myocardial disarray. The genetic analysis of the index patient showed two nucleotide variations in two different genes (ANK2: c.11791G>A, MYO18B: c.3761G>A), which were also expressed in five relatives. Two family members had showed all indicators of the inherited syndrome including distinct ECG changes and genetic changes.

Conclusion: We describe a distinct inheritable syndrome causing SCD, characterized by specific ECG changes and mutations of ANK2 and MYO18. As far as we know this is the first description of this syndrome.

Introduction: Vitiligo is an acquired depigmenting skin disorder due to the loss of melanocyte function in the epidermis and hair follicles. The pathogenesis of vitiligo is multifactorial, with genetics being a predisposing factor. Previous studies had varying results regarding whether or not polymorphisms of vitamin D receptor (VDR) gene are associated with the risk of vitiligo in specific populations. This study investigated the association between three frequently analyzed VDR gene polymorphisms (ApaI, BsmI, TaqI) and susceptibility to vitiligo in Indonesian population.

Methods: Thirty-four vitiligo patients and 34 age- and sex-matched healthy subjects aged ≥18 years old were recruited in the Dermatology and Venereology Outpatient Clinic of Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. Genomic deoxyribonucleic acid (DNA) was extracted from the peripheral blood using a DNA isolation kit. VDR gene polymorphisms (ApaI, BsmI, and TaqI) were investigated using the polymerase chain reaction-restriction-fragment length polymorphism method. The differences of genotype distributions and allele frequencies were statistically compared between case and control groups using Chi-square test.

Results: VDR gene polymorphisms were identified in 68 participants, consisting of Aa (n = 14), aa (n = 20), Bb (n = 15), bb (n = 19), and TT (n = 34) genotypes in the case group. In the control group, Aa (n = 6), aa (n = 28), Bb (n = 17), bb (n = 17), and TT (n = 34) genotypes were identified. However, only subjects with ApaI Aa genotype polymorphism had a 3.267-fold increased risk of developing vitiligo.

Conclusion: This study showed that ApaI Aa genotype polymorphism of the VDR gene increases the risk of vitiligo in Indonesian population.

Background: Hemophilia cannot be diagnosed in most laboratories of economically less-developed countries leading to high mortality and morbidity rates.

Aim: A diagnostic tool was established ranging from bleeding assessment and a simple bedside test of mixing venous clotting time (VCT) to comprehensive DNA analysis for patients with hemophilia.

Methods: Patients with known (n=80) and suspected hemophilia (n=14) were included. Their bleeding symptoms were initially evaluated using verified translated-Thai ISTH bleeding assessment tool. Then, blood samples were drawn using a two-syringe technique, 2 mL each was placed in three tubes, for the mixing VCT and citrate blood was kept for coagulogram and coagulation factor assay. Finally, DNA analysis was determined.

Results: A total of 94 patients with hemophilia (A68, B26) defined as severe (A 57, B 17), moderate (A 7, B 5), and mild degrees (A 4, B 4) with the mean (SD) age of 14.0 (11.7) years and 24 normal controls aged 25.5 (4.5), were enrolled in the study. The mean (SD) bleeding score of patients with hemophilia was 13.5 (5.5), which did not significantly differ between patients with hemophilia A and B. The mixing venous clotting time offered the presumptive diagnosis of hemophilia A and B, which were subsequently confirmed by the prolonged APTT, low FVIII:C and FIX:C and mutations on the factor VIII and IX genes.

Conclusion: A diagnostic tool for bleeding assessment, mixing venous clotting time, coagulogram, coagulation factor assay, and DNA analysis for patients with hemophilia has been established in the existing health-care system.

Introduction: Oncogenetic counseling has been provided at the University Hospital of Bern since 2004. Since the public announcement by Ms. Angelina Jolie in 2013 that she had undergone bilateral prophylactic mastectomy, other oncogenetic centers have reported an increase in consultations. We conducted a retrospective review of the oncogenetic consultations at our center to evaluate the presence and the consequences of a potential "Angelina Jolie effect" and to characterize this patient population over a decade.

Methods: All initial oncogenetic consultations between 2005 and 2015 were collected, using electronic records. Demographics, cancer type, testing, and mutation results, as well as consultation rates, were recorded. The yearly trends were analyzed using Joinpoint regression analysis (JPA).

Results: In total, 823 patient cases were included, mostly women (84%), half of them with a positive personal cancer history. A hereditary breast and ovarian cancer (HBOC) risk was the main reason for consultation (72%). Moreover, 22% of patients had a previously detected familial mutation. Two-thirds underwent testing, which yielded a positive test result in 31% of the cases. According to JPA, the consultation rate increased throughout the decade, with a significant upward trend from 2013. Rates of testing and positive results remained stable over time. Most patients (86%) fulfilled the referral criteria of published guidelines.

Discussion: At our center, we found retrospectively a disproportionate growth in the referral rate for HBOC cases compared to other oncological cases after the year 2013, but overall, no change in testing rates was detected.

Arrhythmogenic cardiomyopathy (AC) is a disease that involves electromechanical uncoupling of cardiomyocytes. This leads to characteristic histologic changes that ultimately lead to the arrhythmogenic clinical features of the disease. Initially thought to affect the right ventricle predominantly, more recent data show that it can affect both the ventricles or the left ventricle alone. Throughout the recent era, diagnostic modalities and criteria for AC have continued to evolve and our understanding of its clinical features in different age groups as well as the genotype to the phenotype correlations have improved. In this review, we set out to detail the epidemiology, etiologies, presentations, evaluation, and management of AC across the age continuum.

Background: Polymorphisms in glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) can cause an entire gene deletion. The current methodology can accurately identify GSTM1 and GSTT1 copy number variants (CNVs), which may shed light on the true contribution of each gene copy to the cellular detoxification process and disease risk. Because liver cirrhosis is becoming a critical worldwide health issue, this study determined the CNVs of GSTM1 and GSTT1 and their relationship to the risk of liver cirrhosis.

Methods: In this study, we compared 106 patients with liver cirrhosis to 104 healthy controls. Real-time PCR was used to identify the CNVs of GSTM1 and GSTT1. Logistic and linear regression models were used to estimate the relationship between liver cirrhosis and clinical chemistry variables with the CNVs, respectively.

Results: In 3.3% of the study participants, >2 copies of the GSTM1 or GSTT1 genes were detected. GSTT1 carriers had a significantly lower risk of liver cirrhosis (p<0.05) compared with individuals who had homozygous deletion (adjusted odds ratio (AOR) = 0.47; 95% CI: 0.25, 0.86). This risk reduction was significant (p<0.05) in patients with a single copy of the GSTT1 gene (AOR = 0.48; 95% CI: 0.25, 0.91). Those with ≥2 copies of combined GSTM1 and GSTT1 also had a significantly (p<0.05) lower risk of developing liver cirrhosis compared with double null genotypes (AOR = 0.38; 95% CI: 0.16, 0.91, p trend <0.001). Moreover, ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a substantial decrease in alanine amino transferase (ALT) and aspartate aminotransferase (AST) levels, respectively.

Conclusion: A single copy number of GSTT1, and ≥2 copies of combined GSTM1 and GSTT1 genes were associated with a reduced risk of liver cirrhosis in Ethiopians. These findings underscore the importance of gene-environment interactions in the multifactorial development of liver cirrhosis.

Sturge-Weber syndrome (SWS) is a congenital, sporadic, and rare neurocutaneous disorder, characterized by the presence of a facial port-wine birthmark (PWB), glaucoma, and neurological manifestations including leptomeningeal angiomatosis and seizures. It is caused by a postzygotic, somatic, gain-of-function variant of the GNAQ gene, and more recently, the GNA11 gene in association with distinctive clinical features. Neuroimaging can help identify and stratify patients at risk for significant complications allowing closer follow-up; although no presymptomatic treatment has been demonstrated to be effective to date, these patients could benefit from early treatment and/or supportive interventions. Choroid plexus (CP) thickness measurements in brain magnetic resonance imaging (MRI) have a high sensitivity and specificity for early and incipient changes in SWS. In contrast, the absence of pathologic findings makes it possible to rule out associated neurological involvement and leads to periodical observation, with new imaging studies only in cases of new clinical signs/symptoms. Periodic ophthalmological examination is also recommended every 3 months during the first year and yearly afterwards to monitor for glaucoma and choroidal hemangiomas. Treatment for SWS depends on the extent and areas that are affected. These include laser surgery for PWB, anticonvulsants in the case of brain involvement, with either seizures or abnormal EEG, and medical treatment or surgery for glaucoma. Sirolimus has been used in a limited number of patients and appears to be a safe and potentially effective treatment for cutaneous and extra-cutaneous features, however controlled clinical studies have not been carried out. Better knowledge of GNAQ/GNA11 molecular pathways will help to develop future targeted treatments.

Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1-9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5-related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.

Owing to their small size and safety profiles, adeno-associated viruses (AAVs) have become the vector of choice for gene therapy applications in the retina. In addition to the naturally occurring AAVs, several engineered variants with enhanced properties are being developed for experimental and therapeutic applications. Nonetheless, there are still some challenges impeding successful application of AAVs for a broader range of retinal gene therapies. The small size of AAV particles ensures efficient tissue transduction but also limits the packaging capacity to a few kilobases. Further, AAV's ability to cross retinal barriers is still an obstacle to pan-retinal transduction of the outer retina with tolerable doses. Lastly, despite overall safety, there have been recent reports of immune responses to AAVs in the eye. Hence, evaluation and prediction of immune responses to AAVs has come to be considered an integral part of future clinical success. This review focuses on the use of AAV in clinical trials for retinal diseases, and discusses developments of variants and novel strategies to overcome immune responses to AAVs.