Principles of clinical genetics for rheumatologists: clinical indications and interpretation of broad-based genetic testing.

Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology.

EVALUATION OF AGREEMENT BETWEEN C/T-13910 POLYMORPHISM GENOTYPING RESULTS AND LACTOSE TOLERANCE TEST RESULTS: A RETROSPECTIVE POPULATION-BASED STUDY IN BRAZIL.

Background: Lactose tolerant test (LTT) is the most broadly used diagnostic test for lactose intolerance in Brazil, is an indirect, minimally invasive and a low-cost test that is widely available in primary care and useful in clinical practice. The C/T-13910 polymorphism in lactase persistence has been well characterized in Caucasian populations, but there are no studies evaluating the concordance between C/T-13910 polymorphism genotyping results and LTT results in Brazil, where the population is highly mixed.

Objective: We aimed to evaluate agreement between presence of C/T-13910 polymorphism genotyping and malabsorption in LTT results.

The hospital Israelita Albert Einstein standards for constitutional sequence variants classification: version 2023.

Background: Next-generation sequencing has had a significant impact on genetic disease diagnosis, but the interpretation of the vast amount of genomic data it generates can be challenging. To address this, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology have established guidelines for standardized variant interpretation. In this manuscript, we present the updated Hospital Israelita Albert Einstein Standards for Constitutional Sequence Variants Classification, incorporating modifications from leading genetics societies and the ClinGen initiative.

Expansion and mechanistic insights into de novo DEAF1 variants in DEAF1-associated neurodevelopmental disorders.

De novo deleterious and heritable biallelic mutations in the DNA binding domain (DBD) of the transcription factor deformed epidermal autoregulatory factor 1 (DEAF1) result in a phenotypic spectrum of disorders termed DEAF1-associated neurodevelopmental disorders (DAND). RNA-sequencing using hippocampal RNA from mice with conditional deletion of Deaf1 in the central nervous system indicate that loss of Deaf1 activity results in the altered expression of genes involved in neuronal function, dendritic spine maintenance, development, and activity, with reduced dendritic spines in hippocampal regions. Since DEAF1 is not a dosage-sensitive gene, we assessed the dominant negative activity of previously identified de novo variants and a heritable recessive DEAF1 variant on selected DEAF1-regulated genes in 2 different cell models.

Parental segregation study reveals rare benign and likely benign variants in a Brazilian cohort of rare diseases.

Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases.

Exome sequencing and targeted gene panels: a simulated comparison of diagnostic yield using data from 158 patients with rare diseases.

Next-generation sequencing (NGS) has altered clinical genetic testing by widening the access to molecular diagnosis of genetically determined rare diseases. However, physicians may face difficulties selecting the best diagnostic approach. Our goal is to estimate the rate of possible molecular diagnoses missed by different targeted gene panels using data from a cohort of patients with rare genetic diseases diagnosed with exome sequencing (ES).

Frequency of carriers for rare recessive Mendelian diseases in a Brazilian cohort of 320 patients.

Several Mendelian disorders follow an autosomal recessive inheritance pattern. Epidemiological information on many inherited disorders may be useful to guide health policies for rare diseases, but it is often inadequate, particularly in developing countries. We aimed to calculate the carrier frequencies of rare autosomal recessive Mendelian diseases in a cohort of Brazilian patients using whole exome sequencing (WES).

Tegumentary manifestations of Noonan and Noonan-related syndromes.

Objectives: Noonan and Noonan-related syndromes are common autosomal dominant disorders with neuro-cardio-facial-cutaneous and developmental involvement. The objective of this article is to describe the most relevant tegumentary findings in a cohort of 41 patients with Noonan or Noonan-related syndromes and to detail certain aspects of the molecular mechanisms underlying ectodermal involvement.

Methods: A standard questionnaire was administered.

A clinical follow-up of 35 Brazilian patients with Prader-Willi syndrome.

Objective: Prader-Willi Syndrome is a common etiology of syndromic obesity that is typically caused by either a paternal microdeletion of a region in chromosome 15 (microdeletions) or a maternal uniparental disomy of this chromosome. The purpose of this study was to describe the most significant clinical features of 35 Brazilian patients with molecularly confirmed Prader-Willi syndrome and to determine the effects of growth hormone treatment on clinical outcomes.

Methods: A retrospective study was performed based on the medical records of a cohort of 35 patients diagnosed with Prader-Willi syndrome.

The first cardiac transplant experience in a patient with mucopolysaccharidosis.

Hunter syndrome (MPSII) is a rare X-linked lysosomal storage disorder that can affect multiple systems but primarily affects the heart. We report the case of a previously asymptomatic 23-year-old patient who had an attenuated form of MPSII and presented with refractory heart failure that required a heart transplant. The diagnosis was confirmed by detection of an increase in urinary excretion of glycosaminoglycans, a deficiency in enzymatic activity, and molecular analysis.

[Aspects of atherosclerosis and metabolic syndrome in lupus erythematosus].

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease affecting mainly young women. In last decades premature atherosclerosis has been identified as an important cause of mortality due to SLE related risk factors (inflammation and treatment) and metabolic syndrome (MS). MS is a group of risk factors, originating from an abnormal metabolism, with an increased risk for developing atherosclerotic cardiovascular disease.