Exome sequencing of 500 Brazilian patients with rare diseases: what we have learned (original) (raw)

Sao Paulo Medical Journal

Dear Editor, Rare diseases comprise a large and diverse group of an estimated 7,000 different conditions that collectively affect millions of people worldwide. We recently studied the genomic findings of 500 Brazilian patients with suspected rare diseases of genetic etiology who have undergone exome sequencing (ES) for diagnostic purposes. 1 We observed an overall diagnostic yield of 31.6% in our cohort. Figure 1-A shows the inheritance patterns of the genetic diseases. These diagnoses were associated with 195 sequence variants, among which 38% were rare variants that have not been previously published in the literature (Figure 1-B). The diagnostic rate varied widely depending on age, and we observed higher diagnostic rates in prenatal samples (67%) and children younger than one year (44%) and lower rates for adults older than 50 years (13%). Undiagnosed patients still comprise the majority of patients in our cohort (68.4%) and remain a challenge in genomics. Even with the advances in genomic technology, for many patients with rare diseases, the diagnostic odyssey has not come to an end. Valuable techniques such as trio exome analysis (testing of samples from a proband and both parents) or genome sequencing may increase the genetic diagnosis of rare diseases. We also found additional genetic alterations that may directly affect the morbidity and mortality of individuals. In 37 patients (7.4%), we found deleterious genetic variants associated with clinically actionable conditions, such as hereditary cancer, arrhythmia, metabolic diseases, and cardiomyopathies. These secondary findings were previously referred to as "incidental findings". (Figure 2). Determining reportable secondary findings remains controversial and challenging. 2-4 Discussions on this subject are prevalent in North American, European, and some Asian countries but have yet to take place in Brazil and other Latin American countries. Indeed, there are no regulatory documents, legislation, or policies from scientific societies in Brazil regarding the protocols for reporting secondary findings in genomic studies. We urge our medical societies to adopt specific policies for reporting these conditions, and more importantly, consider the