Genomic (Brazil)

Over three percent of people carry a dominant pathogenic variant, yet only a fraction of carriers develop disease. Disease phenotypes from carriers of variants in the same gene range from mild to severe. Here, we investigate underlying mechanisms for this heterogeneity: variable variant effect sizes, carrier polygenic backgrounds, and modulation of carrier effect by genetic background (marginal epistasis). We leveraged exomes and clinical phenotypes from the UK Biobank and the Mt. Sinai BioMe Biobank to identify carriers of pathogenic variants affecting cardiometabolic traits. We employed recently developed methods to study these cohorts, observing strong statistical support and clinical translational potential for all three mechanisms of variable carrier penetrance and disease severity. For example, scores from our recent model of variant pathogenicity were tightly correlated with phenotype amongst clinical variant carriers, they predicted effects of variants of unknown significance, and they distinguished gain- from loss-of-function variants. We also found that polygenic scores modify phenotypes amongst pathogenic carriers and that genetic background additionally alters the effects of pathogenic variants through interactions.

Rare diseases include 6,000-8,000 different conditions, over 70% of them having a genetic cause. Most cases have early manifestations (in childhood and adolescence), and just a small fraction (around 5%) has specific therapies available. Nevertheless, appropriate management measures contribute to improve the quality of life of patients and families. They affect up to 3.5-5.9% of the world's population and are recently attracting attention from international agencies such as the United Nations and the World Health Organization. In Brazil, a condition is considered rare when there are no more than 65 people affected in each 100,000 inhabitants and it is estimated that around 12million people in the country may present one of these conditions, which represents a significant burden to the family and to the health care system. Despite concrete advances observed in the last decades, there are still significant unmet needs for persons living with rare diseases in Brazil. With the main aim of shortening the journey of patients with rare diseases in Brazil, we envisioned a model that involves comprehensive clinical and laboratorial multiprofessional evaluations, with intensive use of telemedicine and genomics. The model includes a strong activity in education, training and research, and has several parallel initiatives (biobank, registry, undiagnosed disease program, information services, extramural diagnostic support), in addition to strategic partnerships, that make the overall project stronger. This report describes the system in place at the pilot unit of Casa dos Raros (that started activities in 2023, in Porto Alegre, Brazil) and the stimulating preliminary results, which indicate a significant reduction in the diagnostic journey. This model, that operates as a charity and does not charge any fees to patients and families, will be replicated in other regions of Brazil, with the opening of a second unit planned to occur in the near future in Sao Paulo.

Myhre syndrome is a rare disorder caused by pathogenic gain-of-function variants in the SMAD4 gene. Most of the patients have had de novo variants. There are several instances of autosomal dominant inheritance, and penetrance appears to be complete. We describe seven Brazilian patients, three of whom are siblings carrying the recurrent c.1486C>T p.(Arg496Cys) variant in SMAD4 inherited from the father. The other three patients are unrelated simplex cases. All affected individuals have clinical features commonly found in Myhre syndrome, including typical dysmorphic facial features, with intra- and interfamilial clinical heterogeneity. Five of the patients have developmental delay and/or clinical signs of intellectual disability. However, only one had neuropsychological testing. Only one patient had a diagnosis of autism spectrum disorder. As in previously reported families, this new family has the same c.1486C>T p.(Arg496Cys) variant. This is the first study describing Brazilian patients with Myhre syndrome, highlighting the clinical variability of this rare disease. We reinforce the need to investigate the parents to provide appropriate genetic counseling.

BackgroundThe Human Genome Variation Society (HGVS) Nomenclature is the global standard for describing and communicating variants in DNA, RNA, and protein sequences in clinical and research genomics. This manuscript details recent updates to the HGVS Nomenclature, highlighting improvements in governance, community engagement, website functionality, and underlying implementation of the standard.MethodsThe HGVS Variant Nomenclature Committee (HVNC) now operates under the Human Genome Organization (HUGO), facilitating broader community feedback and collaboration with related standards organizations. The website has been redesigned using modern documentation tools and practices. The specification was updated to include guidance for transcript selection and to align with recent cross-consortia recommendations for the representation of gene fusions. A formal computational grammar was introduced to improve the precision and consistency of variant descriptions.ResultsMajor improvements in HGVS Nomenclature v. 21.1 include a redesigned website with enhanced navigation, search functionality, and mobile responsiveness; a new versioning policy aligned with software management practices; formal mechanisms for community feedback and change proposals; and adoption of Extended Backus-Naur Form (EBNF) for defining syntax. The specification now recommends MANE Select transcripts where appropriate and includes updated guidance for representing adjoined transcripts and gene fusions. All content is freely available under permissive licenses at hgvs-nomenclature.org.ConclusionsThese advancements establish a more sustainable foundation for maintaining and evolving the HGVS Nomenclature while improving its accessibility and utility. The introduction of formal computational grammar marks a crucial step toward unambiguous variant descriptions that can be reliably processed by both humans and machines. Combined with enhanced community engagement mechanisms and improved guidance, these changes position the HGVS Nomenclature to better serve the evolving needs of clinical and research genomics while maintaining the stability that users require.

Recent work has revealed an important role for rare, incompletely penetrant inherited coding variants in neurodevelopmental disorders (NDDs). Additionally, we have previously shown that common variants contribute to risk for rare NDDs. Here, we investigate whether common variants exert their effects by modifying gene expression, using multi-cis-expression quantitative trait loci (cis-eQTL) prediction models. We first performed a transcriptome-wide association study for NDDs using 6987 probands from the Deciphering Developmental Disorders (DDD) study and 9720 controls, and found one gene, RAB2A, that passed multiple testing correction (p = 6.7 × 10–7). We then investigated whether cis-eQTLs modify the penetrance of putatively damaging, rare coding variants inherited by NDD probands from their unaffected parents in a set of 1700 trios. We found no evidence that unaffected parents transmitting putatively damaging coding variants had higher genetically-predicted expression of the variant-harboring gene than their child. In probands carrying putatively damaging variants in constrained genes, the genetically-predicted expression of these genes in blood was lower than in controls (p = 2.7 × 10–3). However, results for proband-control comparisons were inconsistent across different sets of genes, variant filters and tissues. We find limited evidence that common cis-eQTLs modify penetrance of rare coding variants in a large cohort of NDD probands.

Genotype-environment interaction is pervasive in forest genetics. Delineation of spatial breeding zones (BZs) is fundamental for accommodating genotype-environment interaction. Here we developed a BZ classification pipeline for the forest tree Eucalyptus globulus in 2 Australian regions based on phenotypic, genomic, and pedigree data, as well on a detailed environmental characterization (“envirotyping”) and spatial mapping of BZs. First, the factor analytic method was used to model additive genetic variance and site–site genetic correlations (rB) in stem volume across 48 trials of 126,467 full-sib progeny from 2 separate breeding programs. Thirty-three trials were envirotyped using 145 environmental variables (EVs), involving soil and landscape (71), climate (73), and management (1) EVs. Next, sparse partial least squares-discriminant analysis was used to identify EVs that were required to predict classification of sites into 5 non-exclusive BZ classes based on rB. Finally, these BZs were spatially mapped across the West Australian and “Green Triangle” commercial estates by enviromic prediction using EVs for 80 locations and 15 sets of observed climate data to represent temporal variation. The factor analytic model explained 85.9% of estimated additive variance. Our environmental classification system produced within-zone mean rB between 0.76 and 0.84, which improves upon the existing values of 0.62 for Western Australia and 0.67 for Green Triangle as regional BZs. The delineation of 5 BZ classes provides a powerful framework for increasing genetic gain by matching genotypes to current and predicted future environments.