P670: Diagnostic utility of exome sequencing in liver transplant recipients: A single-center experience using a curated Mendelian liver gene list

Introduction: Liver transplantation is the definitive therapy for acute liver failure and end-stage liver disease, significantly improving survival and quality of life.However, genetic or metabolic disorders account for approximately 4-5% of adult and 14-70% of pediatric liver transplants, depending on the study and region, many of which remain undiagnosed at the genetic level.Unrecognized inherited etiologies can lead to pre-and post-transplant complications, including disease recurrence, graft dysfunction, medication interactions, and extra-hepatic comorbidities.Establishing a genetic diagnosis may clarify the cause of liver disease, refine management, inform donor selection, and guide family counseling.Despite the proven utility of exome sequencing (ES) in kidney transplant cohorts, its diagnostic in liver transplant recipients has not been systematically evaluated.This study aimed to determine the diagnostic yield, clinical relevance of ES in liver transplant recipients using a curated list of 502 Mendelian liver disease genes, and to assess the contribution of primary and secondary liver disease genes to transplant indications and associated comorbidities.Methods: ES was performed on 111 adult liver transplant recipients at Columbia University Irving Medical Center (CUIMC) using a curated panel of 502 liver disease-associated genes.In our cohort of 112 patients, 98 underwent liver transplant only, 12 received transplants in two organs, and 2 had transplants in three organs.The cohort included 42 females and 70 males, with a mean age of 55.4 ± 17.7 years.Of the 112 samples, three failed sequencing or had lowquality results.The resulting cohort, self-reported race and ethnicity, comprised 32 participants (28.6%) identifying as Hispanic/Latino of any race, 58 (51.8%) as White, and 9 (8 %) as Black or African American, 8 (7.1 %) as Asian, 1 (0.9 %) as American/Alaska Native, and 4 (3.6%) as Other/Multiracial/ Unknown.Variant filtering included sequencing quality thresholds (QUAL ≥ 50, GQ ≥ 90, DP ≥ 10), exclusion of benign/likely benign variants unless conflicting evidence existed, and minor allele frequency thresholds of ≤10 -4 , while retaining all pathogenic (P) and likely pathogenic (LP) variants regardless of MAF.Variants were classified per ACMG-AMP guidelines as P, LP, or VUS leaning toward likely pathogenic (VUS-LP).Clinical chart review assessed genotype-phenotype concordance and management implications at the time of liver transplantation.Secondary findings were analyzed according to ACMG SF v3.3 recommendations.Results: After manual curation and secondary review, 11 of 109 patients (10.1%) carried P/LP variants in liver disease-associated genes; three additional VUS-LP variants were identified as potential diagnostic candidates.Night P/LP variants were linked to primary liver diseases explaining transplant indications, while two involved genes associated with secondary liver disorders, revealing broader comorbidity and risk associations.Variants in HFE and SERPINA1 were detected in three and two patients, respectively.Most variants were missense (7); four were protein-truncating (one indel and three stopgain).ACMG secondary findings were identified in five patients, including variants in APOB, PTEN, KCNQ1, LDLR, and TNNI3. Conclusion:In this single-center study, ES achieved a 10.1% diagnostic yield for monogenic liver disorders in transplant recipients.Iterative filtering, manual review, and phenotype correlation were essential to reduce false positives and negatives and ensuring accurate diagnosis.These findings underscore that ES can be a powerful tool for both diagnostic evaluation in liver transplant patients, and highlight the need to integrate genetic data into pre and post-transplant care to inform personalized management.