Application of Clinical Genetics

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...

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic imprinting disorders resulting from absent or reduced expression of paternal or maternal genes in chromosome 15q11q13 region, respectively. The most common etiology is deletion of the maternal or paternal 15q11q13 region. Methylation is the first line for molecular diagnostic testing; MS-MLPA is the most sensitive test. The molecular subtype of PWS/AS provides more accurate recurrence risk information for parents and for the individual affected with the condition...

Genetic variants causing loss of sucrase-isomaltase (SI) function result in malabsorption of sucrose and starch components and the condition congenital sucrase-isomaltase deficiency (CSID). The identified genetic variants causing CSID are very rare in all surveyed populations around the globe, except the Arctic-specific c.273_274delAG loss-of-function (LoF) variant, which is common in the Greenlandic Inuit and other Arctic populations. In these populations, it is, therefore, possible to study people with loss of SI function in an unbiased way to elucidate the physiological function of SI, and investigate both short-term and long-term health effects of reduced small intestinal digestion of sucrose and starch...

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...

The introduction and development of genetic testing has caused the emergence of numerous dilemmas, which pertain to the performed tests, their results, and the influence they have on an individual person. To minimize potential doubts, it is crucial to ensure compliance with established procedures and to fulfill all test-associated formalities. In 2018, a report of the Polish Supreme Audit's Office (a governmental control agency) on the quality of genetic tests revealed that there is much to be done in the field of laboratory diagnostics in Poland...

PURPOSE: Noonan syndrome and related disorders are genetic conditions affecting 1:1000-2000 individuals. Variants causing hyperactivation of the RAS/MAPK pathway lead to phenotypic overlap between syndromes, in addition to an increased risk of pediatric tumors. DNA sequencing methods have been optimized to provide a molecular diagnosis for clinical and genetic heterogeneity conditions. This work aimed to investigate the genetic basis in RASopathy patients through Next Generation Sequencing in a Reference Center for Rare Diseases (IFF/Fiocruz) and implement the precision medicine at a public health institute in Brazil...

Objective: The study aimed to report a 3-decade successive establishment of care for women/girls from families with haemophilia. Methods: A retrospective analysis was conducted on 462 women/girls from 243 families from 1987 to 2021. Results: Combining phenotypic analysis of coagulation factor and genotypic analysis of either linkage analysis or mutation detection confirmed the status of all obligate haemophilia carriers (A118, B19). For potential carrier, 159 proven carriers (A130, B29) and 146 noncarrier status (A126, B20) were diagnosed except 20 potential carriers (A16, B4)...

Objective: Trisomy 13 is one of the most common chromosome aberrations diagnosed in the prenatal period, and is associated with some specific dysmorphic features. Rare chromosome 13 aberrations other than trisomy 13 may cause other fetal abnormalities. The aim of the study was to analyze cases with those rare chromosome 13 aberrations. Methods: We analyzed all prenatal tests performed in the Department of Clinical Genetics of the Medical University of Lodz from 2016 to 2021 to find all chromosome 13 aberrations...

We report the finding of two copy number variants (CNVs) in a 12-year-old boy presenting both with autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Clinical features included aggressive behavior, mood instability, suicidal statements, repetitive and restrictive behavior, sensitivity to noise, learning problems and dyslexia, though no intellectual disability was present. Using array-based comparative genomic hybridization (array-CGH), we identified two CNVs, both triplex duplications of 324 kb on 3p26...

Pathogenic variants in the ABCD1 gene on the X chromosome may result in widely heterogenous phenotypes, including adrenomyeloneuropathy (AMN). Affected males typically present in their third or fourth decade of life with progressive lower limb weakness and spasticity, and may develop signs and symptoms of adrenal insufficiency and/or cerebral demyelination. Heterozygous females may be asymptomatic, but may develop a later-onset and more slowly progressive spastic paraparesis. In this review, we describe the clinical presentation of AMN, as well as its diagnosis and management...

Background: We aimed to evaluate the diagnostic roles of AFAP1-AS1 and ASB16-AS1 in colorectal cancer and highlight their roles in predicting colorectal cancer patients' prognosis. Methods: In this case-control study, 146 participants were involved. Group I included 47 patients with CRC. Group II composed of 49 patients with benign lesions in the colon, and Group III included 50 apparently normal subjects of coincided age and gender as controls. All participants were subjected to clinical and endoscopic evaluations, CA19-9, CEA, and quantification of relative expression of lncRNAs ASB16-AS1 and AFAP1-AS1...

OBJECTIVE: To evaluate the utility of measuring fetal cavum septum pellucidum (CSP) width during routine, mid-pregnancy ultrasound for improving diagnosis of 22q11.2 deletion syndrome amongst fetuses with and without conotruncal anomalies. PATIENTS AND METHODS: This was a retrospective case-control study (2005-2016). Fetuses and newborns with 22q11.2 deletion and/or conotruncal cardiac anomalies were identified using a regional, clinical database. A control group was assembled in a 2:1 ratio to create three groups for comparison: i) 22q11...

Background: Acute myeloid leukemia (AML) is of heterogeneous pathogenesis and caused by alterations of multiple genes. CircRNAs act as oncogenes or tumor suppressors in numerous tumors and could be novel diagnostic and prognostic biomarkers. Few studies had incorporated circRNAs in AML. Aim of the Work: Assessment of circANXA2, circ0075001, and circFBXW7 gene expressions in AML patients. Evaluation of their relations with clinical, cytogenetic, and overall survival outcome to emphasize their diagnostic role and prognostic impact...

White-Sutton syndrome is a rare type of autosomal dominant neurodevelopmental disorder caused by mutations, mostly de novo , in the POGZ gene. No more than 120 patients have been described so far in the literature. Common clinical manifestations include intellectual disability, developmental delay, autism spectrum disorder, other behavioral abnormalities, sleeping problems, hyperactivity and visual problems. We describe a 20-year-old male patient from Colombia who presented with delayed psychomotor development, intellectual disability, obesity, sleep difficulties, hypotonia, hypogonadism, gynecomastia, visual abnormalities and several facial dysmorphisms...

Objective: To investigate the relationship between unexplained recurrent pregnancy loss (URPL) and polymorphisms of homocysteine metabolism-related genes in women. Materials and Methods: A case-control study included 90 women with two or more consecutive unexplained pregnancy losses and 92 controlled women without miscarriage history; the female participants were in the age category of 18-35 years. The high-resolution melting technique was used to detect the single-nucleotide variants related to homocysteine metabolism disorder, namely MTHFR C677T, MTHFR A1298C, MTR A2756G, and MTRR A66G polymorphism...

Background: Adequate replacement for patients with hemophilia is costly, especially in countries with limited resources. Objective: Factor VIII gene mutations among Thai patients with hemophilia A were analyzed for the most common mutation. The cost-effectiveness of finding one female without family history of hemophilia possessing the most common factor VIII mutation was compared with the cost of treating one patient with hemophilia. Methods: In all, 109 unrelated patients with hemophilia A, defined as sporadic cases (n=58) and hereditary cases (n=51), were enrolled for genotypic analysis...