Non-coding variants are a rare cause of recessive developmental disorders in trans with coding variants.

PURPOSE: Identifying pathogenic non-coding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic non-coding 'second hits' in trans with these is unknown. METHODS: In 4,073 genetically undiagnosed rare disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes. We identified rare non-coding variants on the other haplotype in introns, untranslated regions (UTRs), promoters, and candidate enhancer regions. We clinically evaluated the top candidates for phenotypic fit, and performed functional testing where possible. RESULTS: We identified 3,761 rare heterozygous loss-of-function or ClinVar pathogenic variants in recessive DD-associated genes in 2,430 probands. For 1,366 (36.3%) of these, we identified at least one rare non-coding variant in trans. Bioinformatic filtering and clinical review, revealed seven to be a good clinical fit. After detailed characterisation, we identified likely diagnoses for three probands (in GAA, NPHP3, and PKHD1) and candidate diagnoses in a further three (PAH, LAMA2, IGHMBP2). CONCLUSION: We developed a systematic approach to uncover new diagnoses involving compound heterozygous coding/non-coding variants and conclude that this mechanism is likely to be a rare cause of DDs.

Markers of adipose tissue fibrogenesis associate with clinically significant liver fibrosis and are unchanged by synbiotic treatment in patients with NAFLD.

BACKGROUND AND AIMS: Subcutaneous adipose tissue (SAT) dysfunction contributes to NAFLD pathogenesis and may be influenced by the gut microbiota. Whether transcript profiles of SAT are associated with liver fibrosis and are influenced by synbiotic treatment (that changes the gut microbiome) is unknown. We investigated: (a) whether the presence of clinically significant, ≥F2 liver fibrosis associated with adipose tissue (AT) dysfunction, differential gene expression in SAT, and/or a marker of tissue fibrosis (Composite collagen gene expression (CCGE)); and (b) whether synbiotic treatment modified markers of AT dysfunction and the SAT transcriptome. METHODS: Sixty-two patients with NAFLD (60 % men) were studied before and after 12 months of treatment with synbiotic or placebo and provided SAT samples. Vibration-controlled transient elastography (VCTE)-validated thresholds were used to assess liver fibrosis. RNA-sequencing and histological analysis of SAT were performed to determine differential gene expression, CCGE and the presence of collagen fibres. Regression modelling and receiver operator characteristic curve analysis were used to test associations with, and risk prediction for, ≥F2 liver fibrosis. RESULTS: Patients with ≥F2 liver fibrosis (n = 24) had altered markers of AT dysfunction and a SAT gene expression signature characterised by enrichment of inflammatory and extracellular matrix-associated genes, compared to those with