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Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy–Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms. [ABSTRACT FROM AUTHOR]

Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy–Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in ADGRG1(p.Arg565Trp) and a novel variant in CNTNAP1(p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.

Abstract Background Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance. Methods The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case–control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network. Results Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers’ immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q

Background: Biliary Atresia (BA) is rare and genetically complex, and the pathogenesis is elusive. The disease course is variable and can represent heterogeneity, which hinders effective disease management. Deciphering the BA phenotypic variance is a priority in clinics and can be achieved by the integrative analysis of genotype and phenotype. We aim to explore the BA phenotypic features and to delineate the source of its variance., Methods: The study is a cross-sectional observational study collating with case/control association analysis. One-hundred-and-eighty-one type III non-syndromic BA patients and 431 controls were included for case-control association tests, including 89 patients (47.19% males, born June 15th, 1981 to September 17th, 2007) have detailed clinical records with follow-up of the disease course (median ~17.2 years). BA-association genes from the genome-wide gene-based association test on common genetic variants (CV) and rare copy-number-variants (CNVs) from the genome-wide survey, the later comprise only CNVs > 100 kb and found in the BA patients but not in the local population (N = 1,381) or the database (N = 11,943). Hereby comorbidity is defined as a chronic disease that affects the BA patients but has no known relationship with BA or with the BA treatment. We examined genotype-phenotype correlations of CNVs, connectivity of these novel variants with BA-associated CVs, and their role in the BA candidate gene network., Results: Of the 89 patients, 41.57% have comorbidities, including autoimmune-allergic disorders (22.47%). They carried 29 BA-private CNVs, including 3 CNVs underpinning the carriers' immunity comorbidity and one JAG1 micro-deletion. The BA-CNV-intersected genes (N = 102) and the CV-tagged genes (N = 103) were both enriched with immune-inflammatory pathway genes (FDR q < 0.20), and the two gene sets were interconnected (permutation p = 0.039). The molecular network representing CVs and rare-CNV association genes fit into a core/periphery structure, the immune genes and their related modules are found at the coherence core of all connections, suggesting its dominant role in the BA pathogenesis pathway., Conclusions: The study highlights a patient-complexity phenomenon as a novel BA phenotypic feature, which is underpinned by rare-CNVs that biologically converge with CVs into the immune-inflammatory pathway and drives the BA occurrence and the likely BA association with immune diseases in clinics.