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Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10–13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing. [ABSTRACT FROM AUTHOR]

Abstract: Background: Classical homocystinuria (HCU) is a monogenic disease caused by the deficient activity of cystathionine β‐synthase (CβS). The objective of this study was to identify the CBS mutations in Brazilian patients with HCU. Methods: gDNA samples were obtained for 35 patients (30 families) with biochemically confirmed diagnosis of HCU. All exons and exon‐intron boundaries of CBS gene were sequenced. Gene expression analysis by qRT‐PCR was performed in six patients. Novel missense point mutations were expressed in E. coli by site‐directed mutagenesis. Results: Parental consanguinity was reported in 16 families, and pyridoxine responsiveness in five (15%) patients. Among individuals from the same family, all presented the same phenotype. Both pathogenic mutations were identified in 29/30 patients. Twenty‐one different mutations were detected in nine exons and three introns; being six common mutations. Most prevalent were p.Ile278Thr (18.2%), p.Trp323Ter (11.3%), p.Thr191Met (11.3%), and c.828+1G>A (11.3%). Eight novel mutations were found [c.2T>C, c.209+1delG, c.284T>C, c.329A>T, c.444delG, c.864_868delGAG c.989_991delAGG, and c.1223+5G>T]. Enzyme activity in E. coli‐expressed mutations was 1.5% for c.329A>T and 17.5% for c.284T>C. qRT‐PCR analysis revealed reduced gene expression in all evaluated genotypes: [c.209+1delG; c.572C>T]; [c.2T>C; c.828+1G>A]; [c.828+1G>A; c.1126G>A]; [c.833T>C; c.989_991delAGG]; [c.1058C>T; c.146C>T]; and [c.444delG; c.444delG]. The expected phenotype according to the genotype (pyridoxine responsiveness) matched in all cases. Conclusions: Most patients studied were pyridoxine nonresponsive and presented early manifestations, suggesting severe phenotypes. Many private mutations were observed, but the four most prevalent mutations together accounted for over 50% of mutated alleles. A good genotype–phenotype relationship was observed within families and for the four most common mutations. [ABSTRACT FROM AUTHOR]