Germline variant analysis from a cohort of patients with severe hypertriglyceridemia in Brazil.

Hypertriglyceridemia (HTG) is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. It is well stablished that the severe cases of disease often present with an underlying genetic cause. In this study, we determined the frequency and variation spectrum of genes involved in the triglyceride metabolism in a series of Brazilian patients with severe HTG. A total of 212 patients with very high HTG, defined with fasting triglycerides (TG) ≥ 880 mg/ dL, that underwent a multi-gene panel testing were included in this research. Germline deleterious variants (i.e. Pathogenic/Likely Pathogenic (P/LP) variants) were identified in 28 out of 212 patients, reflecting an overall diagnostic yield of 13% in our cohort. Variants of unknown significance (VUS) were identified in 87 patients, and represent 80% of detected variants in this dataset. We confirm the LPL as the most frequently mutated gene in patients with severe HTG, and we had only one suspected case of familial chylomicronemia syndrome, caused by a homozygous variant in LMF1, in our cohort. Notably, we report 16 distinct and novel variants (P/LP and VUS), each of them representing a single case, not previously reported in any public databases or other studies. Our data expand our knowledge of genetic variation spectrum in patients with severe HTG in the Brazilian population, often underrepresented in public genomic databases, being also a valuable clinical resource for genetic counseling and healthcare programs in the country.

Whole genome sequencing as a first-tier diagnostic test for infants in neonatal intensive care units: A pilot study in Brazil.

In this pilot study, we aimed to evaluate the feasibility of whole genome sequencing (WGS) as a first-tier diagnostic test for infants hospitalized in neonatal intensive care units in the Brazilian healthcare system. The cohort presented here results from a joint collaboration between private and public hospitals in Brazil considering the initiative of a clinical laboratory to provide timely diagnosis for critically ill infants. We performed trio (proband and parents) WGS in 21 infants suspected of a genetic disease with an urgent need for diagnosis to guide medical care. Overall, the primary indication for genetic testing was dysmorphic syndromes (n = 14, 67%) followed by inborn errors of metabolism (n = 6, 29%) and skeletal dysplasias (n = 1, 5%). The diagnostic yield in our cohort was 57% (12/21) based on cases that received a definitive or likely definitive diagnostic result from WGS analysis. A total of 16 pathogenic/likely pathogenic variants and 10 variants of unknown significance were detected, and in most cases inherited from an unaffected parent. In addition, the reported variants were of different types, but mainly missense (58%) and associated with autosomal diseases (19/26); only three were associated with X-linked diseases, detected in hemizygosity in the proband an inherited from an unaffected mother. Notably, we identified 10 novel variants, absent from public genomic databases, in our cohort. Considering the entire diagnostic process, the average turnaround time from enrollment to medical report in our study was 53 days. Our findings demonstrate the remarkable utility of WGS as a diagnostic tool, elevating the potential of transformative impact since it outperforms conventional genetic tests. Here, we address the main challenges associated with implementing WGS in the medical care system in Brazil, as well as discuss the potential benefits and limitations of WGS as a diagnostic tool in the neonatal care setting.

Clinical and radiological findings in Brazilian patients with mucolipidosis types II/III.

OBJECTIVE: The present study aims to provide orientation for clinicians and radiologists to recognize the most prevalent findings leading to diagnosis in mucolipidosis from a description of the natural history of five Brazilian cases. MATERIALS AND METHODS: We conducted an observational and retrospective study of five patients with clinical and radiological diagnosis of mucolipidosis. Clinical evaluation consisted of information obtained from records and including physical, neurologic, and dysmorphic evaluations. Radiologic studies consisted of complete skeletal radiographs of all patients. Enzyme assessment was performed for confirmation of the diagnosis. RESULTS: The five patients were referred for genetic evaluation due to disproportionate short stature with short trunk accompanied by waddling gait. Age at referral varied from 11 months to 28 years. The most prevalent findings were joint restriction (4/5 patients), neuropsychomotor developmental delay (3/5), coarse facies (2/5), hypertrophic cardiomyopathy (2/5), and mental retardation (1/4 patients). The most common radiological findings were anterior beaking of the vertebral bodies (5/5), shallow acetabular fossae (5/5), epiphyseal dysplasia (5/5), platyspondyly (4/5), pelvic dysplasia (4/5), decreased bone mineralization (4/5), scoliosis (3/5), wide and oar-shaped ribs (3/5), generalized epiphyseal ossification delay (3/5), and hypoplasia of basilar portions of ilea (3/5). Enzyme assessment showed α-iduronidase, α-mannosidase, ß-glucuronidase, hexosaminidase A, and total hexosaminidase increased in plasma and normal glycosaminoglycans concentration. One patient was clinically classified as ML II and four patients as ML III. CONCLUSIONS: The follow-up of five patients showed the typical clinical and radiological findings allowing the diagnosis, thus improving clinical management and providing adequate genetic counseling. Clinicians and radiologists can take advantage of the information from this work, enhancing their differential diagnosis ability.