Clinical description of a homozygous Lys 1169* variant in the DYSF gene associated with autosomal recessive Miyoshi muscular dystrophy type 1: A familial case report.

Miyoshi Muscular Dystrophy Type 1 is a rare autosomal recessive myopathy caused by mutations in the dysferlin (DYSF) gene. This disease presents with progressive distal lower limb weakness, such as gastrocnemius and soleus muscles resulting in difficulty standing on tiptoes, walking, and climbing stairs. We describe a family consisting of 6 siblings, 2 affected males, 1 affected female, 1 affected-death female, and 2 unaffected females. The affected members of this family have lived without an appropriate diagnosis for more than 20 years. Our patients have a homozygous nonsense pathogenic variant of the DYSF gene with 0 frequency in the Genome Aggregation Database. Our study shows that genetic testing provides a crucial aid to doctors when the physical examination and the clinical history are insufficient. It also emphasizes that a precise and accurate diagnosis prompts the correct management of a complex case.

Navigating phenylketonuria management to improve it in Latin America: a systematic literature review and applicability analysis.

Introduction: Phenylketonuria (PKU) is an autosomal recessive metabolic disorder resulting from phenylalanine hydroxylase deficiency, which impacts neurodevelopment. Lifelong low-phenylalanine diets and multidisciplinary care are pivotal for managing PKU. Latin American challenges in PKU care include diverse newborn screening programs, limited specialized healthcare, and resource scarcity. Methods: A systematic literature review was conducted (2010-2023) on PKU management following PRISMA guidelines. Inclusion criteria encompassed English/Spanish articles focusing on PKU management guidelines approved by an organization as well as articles focusing on PKU management in Latin America. After screening 127,276 results, 6 articles were included. Results: Six articles were analyzed, highlighting shared principles like multidisciplinary care, lifelong dietary adherence, personalized plans, and regular monitoring. Guides emphasized regional variations, breastfeeding complexities, and challenges for pregnant women with PKU. Discussion: Multidisciplinary care emerges as critical, incorporating physicians, psychologists, dietitians, nurses, and genetic counselors. Lifelong adherence to low-phenylalanine diets and personalized strategies for different life stages are emphasized. Challenges in Latin America include healthcare gaps, scarce resources, and reliance on international guidance. The importance of breastfeeding, preconception care, and comprehensive support for pregnant women with PKU is underscored. Conclusion: Collaborative efforts are essential to address PKU challenges in Latin America. Advocacy for awareness, specialized training, regional databases, and international collaborations can enhance diagnosis and management, ensuring a better quality of life for PKU individuals in the region. Embracing lessons from existing guides will contribute to improved PKU care and overall well-being.

TTN novel splice variant in familial dilated cardiomyopathy and splice variants review: a case report.

This case report details the identification of a novel likely pathogenic splicing variant in the TTN gene, associated with dilated cardiomyopathy (DCM), in a 42-year-old male patient presenting with early-onset heart failure and reduced ejection fraction. DCM is a nonischemic heart condition characterized by left biventricular dilation and systolic dysfunction, with approximately one-third of cases being familial and often linked to genetic mutations. The TTN gene, encoding the largest human protein essential for muscle contraction and sarcomere structure, is implicated in about 25% of DCM cases through mutations, especially truncating variants. Our investigation revealed a previously unreported G > C mutation at the splice acceptor site in intron 356 of TTN, confirmed by Sanger sequencing and not found in population databases, suggesting a novel contribution to the understanding of DCM etiology. The case emphasizes the critical role of the TTN gene in cardiac function and the genetic complexity underlying DCM. A comprehensive literature review highlighted the prevalence and significance of splice variants in the TTN gene, particularly those affecting the titin A-band, which is known for its role in muscle contraction and stability. This variant's identification underscores the importance of genetic screening in patients with DCM, offering insights into the disease's familial transmission and potential therapeutic targets. Our findings contribute to the expanding knowledge of genetic factors in DCM, demonstrating the necessity of integrating genetic diagnostics in cardiovascular medicine. This case supports the growing evidence linking splicing mutations in specific regions of the TTN gene to DCM development and underscores the importance of genetic counseling and testing in managing heart disease.

AARS and CACNA1A mutations: diagnostic insights into a case report of uncommon epileptic encephalopathy phenotypes in two siblings.

Epilepsy, characterized by recurrent seizures, impacts 70-80% of patients, leading to cognitive deficits. The intricate relationship between seizure control and cognitive impairment remains complex. Epileptic encephalopathy (EE), an intensified form often rooted in genetic factors, is detectable through next-generation sequencing, aiding in precise diagnoses, family counseling, and potential treatment strategies. We present a case involving two sisters with refractory generalized seizures evolving into dysarthria, dysphagia, ataxia, and cognitive decline. Despite normal physical exams, abnormal electroencephalogram results consistent with epilepsy were noted. Whole Exome Sequencing identified heterozygous variants in the alanyl-tRNA synthetase (AARS) and Calcium Voltage-Gated Channel Subunit Alpha 1 (CACNA1A) genes. The AARS variant (c.C2083T, p.R695*) was maternal, while the CACNA1A variant (c.G7400C, p.R2467P) was paternal. Patients A and B exhibited a unique blend of neurological and psychiatric conditions, distinct from common disorders that begin adolescence, like Juvenile Myoclonic Epilepsy. Whole Exome Sequencing uncovered an AARS gene and CACNA1A gene, linked to various autosomal dominant phenotypes. Presence in both parents, coupled with familial reports of migraines and seizures, provides insight into accelerated symptom progression. This study underscores the importance of genetic testing in decoding complex phenotypes and emphasizes the value of documenting family history for anticipating related symptoms and future health risks.

Diagnosis challenges in CHARGE syndrome: A novel variant and clinical description.

Introduction: In resource-limited settings, patients with uncommon phenotypes often face prolonged diagnostic journeys and potential misdiagnoses. Coloboma, heart defects, atresia choanae, restricted growth and development, genital and ear abnormalities syndrome (CHARGE) syndrome, a congenital condition affecting various body parts such as the heart, ears, eyes, and genitals, exemplifies this challenge. Case presentation: We present the case of a 21-year-old male patient from Ecuador who exhibited hypogonadism, facial deformities, and stunted growth. Due to the scarcity of genetic specialists and limited access to genetic testing in Ecuador, the patient received a misdiagnosis of Noonan syndrome. However, a correct diagnosis of CHARGE syndrome was ultimately reached after eight years, facilitated by genetic sequencing that identified a novel mutation in the Chromodomain helicase DNA binding protein 7 gene. Conclusion: This case highlights the critical role of meticulously assessing patients' symptoms and emphasizes the necessity for enhanced collaboration among physicians and researchers. Such efforts are pivotal in advancing healthcare access and equity for individuals in developing nations.

HLA allelic diversity in the Waorani population of Ecuador: Its significance to their ancestry and migration.

The Waorani, an isolated indigenous tribe in Ecuador, have long been characterized by limited genetic diversity, with few studies delving into their genetic background. Human Leukocyte Antigen (HLA) genes which are located in the human major histocompatibility complex (MHC) provides valuable insights into population evolution due to its highly polymorphic nature. However, little is known about the HLA diversity and ancestry of the Waorani population. In this study, we sequenced eight HLA genes using Next Generation Sequencing (NGS) from 134 Waorani individuals and obtained up to four-field HLA allele resolution. Cluster and phylogenetic analysis show that the Waorani are genetically distant from other Ecuador populations, but instead show genetic affinities with the Puyanawa and Terena tribes from Brazil, as well as the Mixe tribe from Mexico. The identification of alleles common within the Waorani population, previously linked to specific health conditions, notably paves the way for future association analyses. This extensive study, employing Next-Generation Sequencing (NGS) technology, significantly enriches the sparse and segmented understanding of HLA diversity in the South American region. Our findings enhance the global comprehension of human genetic diversity and underscore the value of studying indigenous populations. Such research is vital for deepening our insights into human migration patterns and evolutionary processes.