アラジール症候群

Multiplexed assays of variant effects (MAVEs) represent a powerful approach to providing functional information for variants at scale. To harness the full utility of these systems, assay readout must be translated into a language that is accommodating to the clinical genomics community. We previously performed a MAVE to characterize variants in JAG1, the primary cause of the autosomal-dominant, multisystemic disease Alagille syndrome. Using this existing dataset, we calculated log-likelihood ratios of pathogenicity for each variant score, allowing for direct translation of variant data into recognized evidence weights utilized by the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) in clinical variant classification. Calibration resulted in improved separation of known benign and pathogenic variants and increased the classification rate of abnormal missense variants from 486 to 610, providing clear binning for strong (n = 1), moderate (n = 340), and supporting (n = 269) evidence toward pathogenicity. Retrospective application of this evidence to a cohort of 29 individuals with a JAG1 variant of uncertain significance (VUS) identified from clinical diagnostic sequencing yielded nine (31%) variants with abnormal data meeting supporting (n = 3) and moderate (n = 6) weight for pathogenicity, of which six (21%) were upgraded to likely pathogenic or pathogenic. Calibration of MAVE data to comply with the ACMG/AMP variant classification framework improves the diagnostic yield for JAG1 variants for Alagille syndrome. Moreover, our results support the broader application of these models to additional MAVEs, suggesting that they are likely to strongly impact variant classification across genes associated with disease.

UNLABELLED: Alagille syndrome (ALGS) is an autosomal dominant disorder characterized by intrahepatic bile duct insufficiency, cardiac, skeletal, ocular, and characteristic facial features, most commonly caused by pathogenic variants in the JAG1gene and, less frequently, in the NOTCH2 gene. This study aimed to expand the existing literature by reporting novel JAG variants identified in our cohort. This retrospective cross-sectional study included 17 patients diagnosed withALGS between 2010-2025 at the Pediatric Gastroenterology, Hepatology, and Nutrition Clinic of İnönü University Faculty of Medicine. Genetic analysis was performed in 12 patients using JAG1 gene sequencing (n = 6), a targeted cholestasis gene panel (n = 4), or whole-exome sequencing (n = 2). Symptom onset ages ranged from 1 to 150 days. Cholestasis was the most common initial presentation, observed in 13 patients (76.5%). Peripheral pulmonary stenosis was the most frequent cardiac anomaly, identified in 12 patients (70.6%). A molecular diagnosis was established in 12 patients, while five were diagnosed clinically due to the unavailability of genetic testing at presentation. All genetically tested patients harbored pathogenic variants in the JAG1 gene. Ten variants were point mutations and two were large deletions. Five point mutations were classified as novel, as they had not been previously reported in the literature or genomic databases. Additionally, two large deletions involving previously undescribed genomic regions were identified and reported for the first time. CONCLUSIONS: Alagille syndrome should be considered in patients with unexplained cholestasis, especially in populations with high rates of consanguineous marriage, and the diagnosis should be confirmed with genetic testing whenever possible. This study introduces 5 novel variants and two major deletions containing previously unidentified genomic regions to the literature for the first time. WHAT IS KNOWN: • Alagille syndrome (ALGS) is a multisystem disorder most commonly caused by pathogenic JAG1 variants. • Syndromic cholestasis requires early multidisciplinary evaluation and genetic confirmation. WHAT IS NEW: • Five point mutations were classified as novel, as they had not been previously reported in the literature or genomic databases. • Two large deletions involving previously undescribed genomic regions were identified and reported for the first time.

Craniofacial skeletal morphogenesis depends on tightly coordinated interactions between vascular development and osteogenesis. Although congenital craniofacial malformations are traditionally conceptualized as bone-intrinsic disorders, emerging molecular evidence suggests that dysregulated vascular pathways may contribute to skeletal maldevelopment. Here, we synthesize emerging experimental and genetic evidence linking perturbations in vascular development to congenital craniofacial osseous phenotypes. A structured literature search was conducted in PubMed and Embase to identify experimental and genetic studies investigating developmental and vascular associations between vascular dysgenesis and craniofacial bone development. Six studies met the inclusion criteria. Within these studies, vascular dysgenesis was implicated in multiple craniofacial phenotypes. Hemifacial microsomia was linked to mandibular arterial abnormalities and susceptibility loci associated with vasculogenesis. Alagille syndrome demonstrated disrupted palatal vascular branching driven by Jagged1-Notch signaling perturbation. Across models, altered regulation of VEGF isoforms, Neuropilin-1, Jagged1-Notch signaling, and EPAS1-associated pathways impaired pharyngeal arch vascular remodeling, mandibular arterial stability, or vascular branching architecture. These vascular disturbances were associated with phenotypes including micrognathia, cleft palate, hemifacial microsomia, and 22q11.2 deletion syndrome-like features. In contrast, conditions including achondroplasia and cleidocranial dysplasia appear predominantly driven by bone-intrinsic mechanisms without demonstrated vascular involvement. Collectively, the available evidence suggests emerging developmental associations between dysregulated vascular signaling and craniofacial osteogenesis through a potential vascular-osteogenic interface. Although the temporal hierarchy, causality, and lineage-specific mechanisms remain unresolved, recognition of this interface provides a conceptual developmental perspective for future experimental studies investigating endothelial-osteogenic interactions during craniofacial morphogenesis.

Background and Clinical Significance: Biliary atresia (BA) and Alagille syndrome (ALGS) represent distinct anatomic and genetic causes of neonatal cholestasis. Their overlapping clinical, biochemical, and early histological features present a formidable diagnostic challenge in early infancy, and their simultaneous coexistence is exceedingly rare. This report documents a unique case of dual diagnosis to highlight the associated diagnostic pitfalls and implications for surgical management. Case Presentation: We present the case of a Taiwanese male neonate who manifested prolonged jaundice and acholic stools. Preoperative imaging and intraoperative cholangiography confirmed biliary atresia, for which the patient underwent a Kasai portoenterostomy. The patient subsequently exhibited an atypical postoperative course characterized by persistent hyperbilirubinemia and intractable pruritus. This atypical trajectory prompted an extensive, multisystem evaluation and molecular genetic analysis, revealing a concurrent genetic diagnosis of Alagille syndrome. To our knowledge, this dual diagnosis is rarely reported in the literature, which creates a significant challenge in determining surgical candidacy and predicting long-term liver health outcomes. Discussions: Early differentiation is complicated by the fact that some ALGS patients can initially mimic BA. Beyond its exceptional rarity, this case holds profound clinical significance for the evaluation of neonatal cholestasis, serving as a stark reminder of the risks of "diagnostic premature closure." In diagnostically challenging cases of neonatal cholestasis, intraoperative biliary exploration remains the gold standard for the timely diagnosis of BA. Genetic testing should be considered an adjunctive tool when clinical and histological findings are inconclusive. Conclusions: This case highlights a critical clinical caveat in neonatal cholestasis: while a confirmed diagnosis of anatomical BA typically stands alone as a solitary pathology, clinicians should remain mindful of the remote possibility of a concurrent genetic etiology like ALGS in highly atypical presentations. Persistently unexpected postoperative jaundice or the accumulation of multisystem anomalies should prompt an expansion of the differential diagnosis. Recognizing this rare coexistence is crucial for effective multidisciplinary management, informed surgical decision-making, and accurate genetic counseling.

BACKGROUND: Monogenic causes of focal segmental glomerulosclerosis (FSGS) are increasingly recognized, but data from highly consanguineous Middle Eastern populations remain limited. This study explored the diagnostic yield and descriptive genotype-phenotype correlations of a targeted gene panel in Iraqi patients with biopsy-proven FSGS from a cohort enriched for familial, early-onset, and consanguineous disease. METHODS: Thirty consecutive patients with histologically confirmed FSGS underwent next-generation sequencing using a 98-gene renal disease panel. Variants were classified according to ACMG guidelines and interpreted with clinical and histopathological findings. Exploratory analyses compared variant-positive and variant-negative patients and assessed simple clinical predictors of a positive genetic result. RESULTS: Pathogenic variants were identified in 10 of 30 patients (33.3%) in COL4A3 (n = 2), COL4A4 (n = 3), JAG1 (n = 3), and NPHS2 (n = 2). Two novel frameshift variants were detected in COL4A4 (c.3109_3110delCT) and JAG1 (c.1713delC). Variant-positive patients had earlier disease onset than variant-negative patients (20.6 ± 7.2 vs. 30.1 ± 11.6 years; p = 0.022). In this small, enriched cohort, a simple triage rule based on age of onset <25 years, extrarenal manifestations, or family history showed 100% sensitivity and negative predictive value, but requires external validation before clinical use. Gene-group analyses suggested collagen IV-related disease, recessive podocytopathy, and Alagille-spectrum disease in relevant subgroups. CONCLUSIONS: In this predominantly familial and early-onset FSGS cohort, one-third of patients harbored pathogenic variants, supporting the value of gene-panel testing in selected young or syndromic patients while underscoring the need for validation in larger, more representative cohorts.