アラジール症候群

Cholestasis is caused by genetic disorders in 25% of cases. Our study aimed to describe the clinical and genetic profile of cholestasis and to demonstrate the importance of next-generation sequencing (NGS) in the etiologic diagnosis of genetic cholestasis. We included patients referred for cholestasis over a 10-year period. Molecular studies using NGS consisted of a 292-gene panel and/or whole exome sequencing. Our cohort included 70 patients from 66 unrelated families. A genetic diagnosis was established in 70% of the families. The most common diagnoses were Type 2 progressive familial intrahepatic cholestasis (n = 12), neonatal sclerosing cholangitis (n = 4), low phospholipid-associated cholelithiasis syndrome (n = 4), and Alagille syndrome (n = 4). The ABCB11 gene was most frequently mutated (15/46), with two recurrent variants, c.1062T>A (p.Tyr354*) and c.1826_1827dup (p.Ile610Glnfs*45), found in six and four families, respectively. Our results showed a 62% diagnostic yield of molecular testing using NGS in cholestasis. An accurate diagnosis was key to providing appropriate genetic counseling, guiding screening of variant carriers, and prenatal diagnosis.

Genetic testing plays an important role in the diagnosing of liver diseases, but its diagnostic performance varies across patient populations. By analyzing diagnostic yield across patient subgroups, this study aims at defining age-tailored diagnostic workflows for a more effective integration of genetic testing into clinical practice. We retrospectively analyzed 203 patients (145 children, 58 adults) with acute or subacute liver disorders of suspected genetic origin who underwent next-generation sequencing, categorized them by clinical diagnosis, and evaluated diagnostic yields to develop age-tailored testing workflows. The median age was 8 years; 65.5% were male, 84.7% White, and 27.6% had undergone liver transplantation. Cholestatic liver disorders (30%) and unexplained liver dysfunction (20.2%) were the most common indications for testing. Overall, genetic testing achieved a definitive diagnosis in 35.5% of patients, with a higher yield in children than adults (41.4% vs. 20.7%). Metabolic disorders had the highest diagnostic yield (83.3%), while PFIC/BRIC and Alagille syndrome were the most frequent genetic diagnoses. Age-specific diagnostic workflows retrospectively enriched the overall diagnostic rate by approximately 11% across age and disease categories. These findings demonstrate that tailoring genetic testing strategies to patient age and clinical presentation can improve diagnostic efficiency and support a standardized integration of genetic testing into hepatology practice.

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies.In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA-related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.

Alagille syndrome, also known as arteriohepatic dysplasia, is a multisystem genetic disorder inherited in an autosomal dominant pattern. It is primarily caused by mutations in the Jagged canonical Notch ligand 1 (JAG1) gene and is classically diagnosed in childhood with cholestasis due to bile duct paucity. Adult presentation is rare owing to its incomplete penetrance and milder phenotypes. We report a case of a 33-year-old male with recurrent cholestasis and no prior history of childhood jaundice. Common acquired etiologies were excluded, and comprehensive evaluation revealed a JAG1 mutation by whole exome sequencing (WES). Multiorgan screening showed no extrahepatic involvement. Treatment with ursodeoxycholic acid (UDCA) and supportive therapy led to clinical and biochemical resolution. This case emphasizes the significance of considering rare genetic disorders in adults with unexplained recurrent cholestasis and highlights the value of molecular diagnostics such as whole exome sequencing in facilitating timely diagnosis.

PURPOSE: Alagille syndrome (ALGS) is an autosomal dominantly inherited disorder primarily caused by mutations in the Jagged Canonical Notch Ligand 1 (JAG1) gene. Although many pluripotent stem cells are well established, no patient-derived stem cells from exfoliated deciduous teeth (SHED) have been developed. In this study, we aimed to establish SHED from an ALGS patient carrying a heterozygous JAG1mut mutation. METHODS: We isolated SHED from a deciduous tooth of an ALGS patient with a heterozygous JAG1 mutation (ALGS-SHED) by the colony-forming unit-fibroblast (CFU-F) method. We then compared the characteristics of ALGS-SHED and healthy donor-derived control SHED (CONT-SHED). RESULTS: ALGS-SHED displayed mesenchymal stem cell features as indicated by CFU-F formation, immunophenotype, and mesenchymal multipotency into adipocytes, chondrocytes, and osteoblasts. ALGS-SHED showed reduced population doubling capacity and exhibited induced chondrogenic potency and diminished osteogenic potency, but similar hepatic potency. ALGS-SHED damaged in situ potency to form bile duct-like tubular structures in the livers of chronically CCl4-injured mice. CONCLUSIONS: We successfully established ALGS-SHED from an ALGS patient carrying a heterozygous JAG1 mutation. Our established ALGS-SHED may represent a potential model for studying ALGS involving a JAG1 mutation.