👤 Claudia La Mantia

To execute a large-scale, decentralized, clinical-grade whole exome sequencing study, coined Tapestry, for clinical practice, research discovery, and genomic education. Between July 1, 2020, and May 31, 2024, we invited 1,287,608 adult Mayo Clinic patients to participate in Tapestry. Of those contacted, 114,673 patients were consented and 98,222 (65.2% women) are currently enrolled: 62,495 (63.6%) were recruited from Minnesota-, 18,353 (18.7%) from Florida- and 17,374 (17.7%) from Arizona-based practices. Saliva from participants was used to extract DNA, and whole exome sequencing plus ∼300,000 single nucleotide polymorphisms (ie, Exome+ assay) were sequenced by a clinical lab. Results for the Centers for Disease Control and Prevention Tier 1 genes (eg, hereditary breast, ovarian cancer syndrome: BRCA1/2; Lynch syndrome: MLH1, MSH2, MSH6, PMS2, and EPCAM; and familial hypercholesterolemia: APOB, LDLR, PCSK9, and LDLRAP1) were interpreted and entered into the electronic health record. The median age of participants was 59.1 years and ∼11% were from racial/ethnic groups under-represented in research. One thousand eight hundred nineteen (1.9%) participants had actionable pathogenic or likely pathogenic variants (50.0% BRCA1/2, 28.4% familial hypercholesterolemia, and 22.2% Lynch syndrome). Positive results were communicated by genetic counselors who educated patients and providers. Thus far, 62,758 patients' Exome+ assays are stored for research, and the Tapestry Data Access Committee has received 118 requests from investigators, of which 82 have been approved, resulting in the delivery of 1,117,410 Exome+ assays to researchers. A large, decentralized, clinical Exome+ assay study in a tertiary medical center detects actionable germline variants, educates patients as well as providers, and offers access to big data for discovery that advances human health. clinicaltrials.gov Identifier: NCT05212428. Show less

NAFLD patients usually have an increase in AST/ALT levels, but cholestasis can also be observed. We aimed to assess in subjects with NAFLD the impact of the (cholestatic) C pattern on the likelihood of developing major liver-related outcomes (MALO). Five hundred and eighty-two consecutive patients with biopsy-proven NAFLD or a clinical diagnosis of NAFLD-related compensated cirrhosis were classified as hepatocellular (H), C and mixed (M) patterns, by using the formula (ALT/ALT Upper Limit of Normal-ULN)/(ALP/ALP ULN). MALO were recorded during follow-up. An external cohort of 1281 biopsy-proven NAFLD patients was enrolled as validation set. H, M and C patterns were found in 153 (26.3%), 272 (46.7%) and 157 (27%) patients respectively. During a median follow-up of 78 months, only 1 (0.6%) patient with H pattern experienced MALO, whilst 15 (5.5%) and 38 (24.2%) patients in M and C groups had MALO. At multivariate Cox regression analysis, age >55 years (HR 2.55, 95% CI 1.17-5.54; p = .01), platelets <150 000/mmc (HR 0.14, 95% CI 0.06-0.32; p < .001), albumin <4 g/L(HR 0.62, 95% CI 0.35-1.08; p = .09), C versus M pattern (HR 7.86, 95% CI 1.03-60.1; p = .04), C versus H pattern(HR 12.1, 95% CI 1.61-90.9; p = .01) and fibrosis F3-F4(HR 35.8, 95% CI 4.65-275.2; p < .001) were independent risk factors for MALO occurrence. C versus M pattern(HR 14.3, 95% CI 1.90-105.6; p = .008) and C versus H pattern (HR 15.6, 95% CI 2.10-115.1; p = .0068) were confirmed independently associated with MALO occurrence in the validation set. The immunohistochemical analysis found a significantly higher prevalence of moderate-high-grade ductular metaplasia combined with low-grade ductular proliferation in C pattern when compared with the biochemical H pattern. Gene expression analysis showed a lower expression of NR1H3, RXRα and VCAM1 in patients with the C pattern. The presence of a cholestatic pattern in patients with NAFLD predicts a higher risk of MALO independently from other features of liver disease. Show less