Application of Clinical Genetics

Tuberculosis remains a global health concern, with substantial mortality rates worldwide. Genetic factors play a significant role in influencing susceptibility to tuberculosis. This review examines the current progress in studying polymorphisms within immune genes associated with tuberculosis susceptibility, focusing on African populations. The roles of various proteins, including Toll-like receptors, Dendritic Cell-Specific Intercellular Adhesion Molecule-3 Grabbing Non-Integrin, vitamin D nuclear receptor, soluble C-type lectins such as surfactant proteins A and D, C-type Lectin Domain Family 4 Member E, and mannose-binding lectin, phagocyte cytokines such as Interleukin-1, Interleukin-6, Interleukin-10, Interleukin-12, and Interleukin-18, and chemokines such as Interleukin-8, monocyte chemoattractant protein 1, Regulated upon activation, normal T-cell expressed and secreted are explored in the context of tuberculosis susceptibility...

Mutations in the lecithin-cholesterol acyltransferase ( LCAT ) gene, which catalyzes the esterification of cholesterol, result in two types of autosomal recessive disorders: Familial LCAT deficiency (FLD) and Fish Eye Disease (FED). While both phenotypes are characterized by corneal opacities and different forms of dyslipidemia, such as low levels of high-density lipoprotein-cholesterol (HDL-C), FLD exhibits more severe clinical manifestations like splenomegaly, anemia, and renal failure. We describe the first clinically and genetically confirmed case of FLD in Colombia which corresponds to a 46-year-old woman with corneal opacity, hypothyroidism, and dyslipidemia, who does not have any manifestations of renal failure, with two pathogenic heterozygous missense variants in the LCAT gene: LCAT (NM_000229...

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...

OBJECTIVE: We evaluate whether next-generation sequencing (NGS)-based preimplantation genetic testing for aneuploidy (PGT-A) improves the cumulative pregnancy outcomes of patients with unexplained recurrent implantation failure (uRIF) as compared to conventional in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI). PATIENTS AND METHODS: This was a retrospective cohort study (2015-2022). A total of 705 couples diagnosed with uRIF were included in the study...

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...

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...

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...

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...

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...

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...

BACKGROUND: Bilateral secondary angle closure glaucoma is a presenting symptom of microspherophakia and ectopia lentis. Characterizing the associated syndrome and confirmation by genetic testing can identify associated systemic abnormalities and provide appropriate genetic counseling. CASE PRESENTATION: A 42-year-old woman with severe intellectual disability presented with light perception visual acuity and glaucoma, with intraocular pressure (IOP) in her right and left eyes of 69 and 70 mmHg, respectively...

BACKGROUND: The Y chromosome has a specific region, namely the Azoospermia Factor (AZF) because azoospermia is typically reported in the microdeletion of the AZF region. This study aims to assess the characteristics of AZF microdeletion after screening a massive number of low sperm concentration men; and the Microdissection testicular sperm extraction (mTESE) outcomes for retrieving sperm from azoospermic patients. MATERIALS AND METHODS: This retrospective multiple-center study enrolled a total of 1121 men with azoospermia, cryptozoospermia, and severe oligozoospermia from December 2016 to June 2022...

Familial adenomatous polyposis (FAP) is an autosomal dominant cancer predisposition syndrome marked by extensive colorectal polyposis and a high risk of colorectal cancer (CRC). Having access to screening and enrollment programs can improve survival for patients with FAP by enabling them to undergo surgery before the development of colorectal cancer. Provided that there are a variety of surgical options available to treat colorectal polyps in patients with adenomatous polyposis, the appropriate surgical option for each patient should be considered...

INTRODUCTION: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1 , and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function. OBJECTIVE: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia...

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...

INTRODUCTION: BRAF V600E and RAS mutations are the most common gene mutations in papillary thyroid carcinoma (PTC) that may be correlated with its biological behavior. There are still limited data about BRAF V600E and RAS mutations in Indonesia. This study aims to determine the prevalence of BRAF V600E and RAS mutations, and their association with clinicopathologic characteristics. METHODS: Patients who had total thyroidectomy from 2019 to 2021 and those who met our study criteria underwent PCR and DNA sequencing analysis for BRAF V600E, BRAF K601E, exon 2 and 3 of NRAS, HRAS , and KRAS ...

The yield of genetic prenatal diagnosis has been notably improved by introducing whole genome chromosomal microarray (CMA) and prenatal exome sequencing (pES). However, together with increased numbers of diagnoses made, the need to manage challenging findings such as variants of unknown significance (VUS) and incidental findings (IF) also increased. We have summarized the current guidelines and recommendations and we have shown current solutions used in our tertiary center in the Netherlands. We discuss four of the most common clinical situations: fetus with normal pES results, fetus with a pathogenic finding explaining the fetal phenotype, fetus with a variant of uncertain clinical significance fitting the phenotype and fetus with a variant leading to an incidental diagnosis...

BACKGROUND: BRCA1 and BRCA2 genes represent the most investigated breast and ovarian cancer predisposition genes. Ten cases of pathogenic de novo BRCA1 variations and six cases of pathogenic de novo BRCA2 variation have been reported at present. Here, we report a new case of a de novo BRCA1 gene mutation. CASE PRESENTATION: A 30-year-old woman with no health issues and no family history for hereditary breast and ovarian cancer was diagnosed with a hormone receptor positive/HER2 negative invasive breast cancer...

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...

BACKGROUND: Protein MUTYH, encoded by the gene MUTYH, is an important mismatch repair enzyme in the base-excision repair pathway of DNA repair. When genetically altered, different neoplastic conditions can arise. One of the widely known syndromes associated with MUTYH mutations is MUTYH -associated polyposis, a form of familial colorectal cancer syndrome. MUTYH may also be a driver in other familial cancer syndromes, as well as breast cancer and spontaneous cancer cases. However, some controversies about the role of these alterations in oncogenesis remain, especially when affected in a heterozygous way...