Rare diseases impact the lives of 300 million people in the world. Rapid advances in bioinformatics and genomic technologies have enabled the discovery of causes of 20–30% of rare diseases. However, most rare diseases have remained as unsolved enigmas to date. Newer tools and availability of high throughput sequencing data have enabled the reanalysis of previously undiagnosed patients. In this review, we have systematically compiled the latest developments in the discovery of the genetic causes of rare diseases using machine learning methods. Importantly, we have detailed methods available to reanalyze existing whole exome sequencing data of unsolved rare diseases. We have identified different reanalysis methodologies to solve problems associated with sequence alterations/mutations, variation re-annotation, protein stability, splice isoform malfunctions and oligogenic analysis. In addition, we give an overview of new developments in the field of rare disease research using whole genome sequencing data and other omics.

Germline deletions of UDP-glycosyltransferase (UGT) UGT2B17 and UGT2B28 genes are common in human populations, yet their association with aging remains unclear. In this exploratory study, we analyzed data from 12,934 participants, mostly Caucasian, in the Canadian Longitudinal Study on Aging (CLSA) to assess cross-sectional and prospective associations between UGT deficiencies and aging-related health outcomes, including mortality, multimorbidity, allostatic load, disease burden and polypharmacy. Sex-specific associations emerged from cross-sectional analyses: UGT2B17-deficient males were less likely to report arthritis (adjusted odds ratio (OR_adj) = 0.73, 95% confidence interval (0.58-0.92), P = 0.008), UGT2B17-deficient females were less likely to report neurological problems (OR_adj = 0.69 (0.51-0.91), P = 0.01), and UGT2B28-deficient females were less likely to report thyroid disorders (OR_adj = 0.50 (0.29-0.82), P = 0.009). Despite these associations, multimorbidity remained prevalent across all groups and no significant associations were observed with all-cause mortality or longevity. Physiological dysregulation, assessed by the allostatic load index, was more prevalent in males. Among males aged ≥ 65, UGT2B28-deficiency was associated with reduced high dysregulation compared to UGT-proficient males (40.0% vs. 53.0%, P = 0.05), whereas UGT2B17 deficiency was associated with a higher prevalence in males (60.4% vs. 53.0%, P = 0.03). In addition, UGT2B17-deficient males had a lower prevalence of polypharmacy than UGT-proficient males (9.3% vs. 13.9%; P = 0.02). Overall, these findings indicate sex-specific associations between UGT2B17 and UGT2B28 deletions and selected healthspan-related phenotypes, suggesting that UGT-related genetic variation may modulate physiological pathways relevant to aging. Given the exploratory nature of this study and its reliance on prevalence data, the results are intended to be hypothesis-generating and will require confirmation in longer-term longitudinal studies.