Victor Chang Cardiac Research Institute

The spectrum of congenital malformations in VACTERL association varies among patients and can be differentially diagnosed with CHARGE syndrome, Fanconi anaemia, and others (reviewed in Solomon 2011). Despite overlapping clinical findings, the genetic causes of these diseases are distinct. In this context, unbiased whole genome sequencing can assist in differential diagnoses, as well as identify new gene-disease associations. In this report, we demonstrate that whole genome sequencing of a proband with suspected VACTERL association revealed two gene variants in the ribosomal genes RPL18 (NM_000979.4 c.397 G > C p.(Gly133Arg)) and RPS6 (NM_001010.3: c.370 C > G p.(Leu124Val)). Mutations in ribosomal genes are associated with Diamond-Blackfan anaemia, a condition that shares phenotypic similarities with Fanconi anaemia. Our modelling and functional assessment of the identified variants strongly indicate pathogenicity of the RPL18:p.(G133R) variant as it is novel, displays reduced expression and stability and abnormal intracellular distribution, and interferes with protein synthesis in cultured cells. The RPS6:p.(L124V) variant reduced protein expression and altered cytoplasmic distribution but does not interfere with protein synthesis in cultured cells. Overall, our study indicates the significant advantage of using unbiased whole genome sequencing for the examination of patients with complex congenital malformations.

Background: Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource (ClinGen) evaluation, the DCM Gene Curation Expert Panel (GCEP) reconvened in 2024-2025 to conduct a reassessment of genes in DCM. Methods: The ClinGen semi-quantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories based upon strength of published evidence for a DCM phenotype. Previously curated genes were reassessed and newly reported gene-disease-mode of inheritance (MOI) relationships, termed ?curations,? were evaluated. Results: Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence, including BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five re-evaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2, for which curation was modified to separate autosomal dominant (-AD) and -AR MOI curations, clinically significant changes involved upgrades from low to high evidence categories (PLEKHM2, PRDM16, TBX20, TNNI3K), demonstrating the robustness of the ClinGen gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including six newly evaluated genes and one new MOI for a previously evaluated gene, MYBPC3-AR; four were classified as No Known Disease Relationship, and four remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs, including JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong). Conclusions: With substantial new evidence, the genetic architecture of DCM has rapidly expanded. This updated assessment of genes reported in DCM yielded 35 high evidence curations, an increase from 19 only five years ago. The results of this evidence-based evaluation process informs clinical interpretation of genetic information in the care of DCM patients and families.

ABSTRACTObjectiveTo describe the clinical and demographic profile of Australian children first diagnosed with acute rheumatic fever (ARF) or rheumatic heart disease (RHD) before the age of 5 years, with comparison to children aged 5–14 years.MethodsLinked emergency department, hospitalisation, RHD register and death records from the End RHD in Australia: Study of Epidemiology were used to identify first ARF/RHD diagnosis occurring in < 15‐year‐olds. Demographic/clinical profiles and pre‐diagnosis healthcare interactions were analysed with stratification into 5‐year age groups.DesignRetrospective cross‐sectional linked administrative data analysis.SettingNorthern Territory, South Australia, Queensland and Western Australia.ParticipantsChildren aged < 15 years at first hospitalisation or notification for ARF or RHD, 2001–2017.Main Outcome MeasuresDisease stage and severity at diagnosis, register notification status, clinical history prior to ARF or RHD diagnosis.ResultsOf 2382 children diagnosed with ARF/RHD aged < 15 years, 180 (7.6%) were aged under 5 years. Among under 5‐year‐olds with ARF or RHD, 30.6% had not been notified to RHD registers. A total 49 under 5‐year‐olds were diagnosed with RHD; with 22 (44.9%) classified as having mild disease, 16 (32.7%) moderate and 6 (12.2%) severe. High hospitalisation rates for injury in the first year of life were observed for the < 5‐year‐old cohort with ARF/RHD.ConclusionsWe present the first comprehensive Australian evidence that ARF and RHD diagnoses are occurring in Australian children aged under 5 years. Greater awareness among clinicians is needed regarding ARF/RHD as a potential diagnosis in this young, high risk age group.

Sulfate-reducing bacteria import organosulfur compounds from the environment for anaerobic respiration. They contribute to human disease and are problematic in industrial settings because they produce hydrogen sulfide. Here, we demonstrate how the sulfate-reducing bacterium Oleidesulfovibrio alaskensis imports isethionate, a common organosulfonate, using a tripartite ATP-independent periplasmic (TRAP) transporter (OaIsePQM). The cryo-EM structure of isethionate-bound OaIseQM to 2.98 Å resolution defines the substrate-binding site, two Na+-binding sites, and a distinct fusion helix. Key residues within the OaIseQM substrate-binding site are identified using substitution and proteoliposome assays. Functional studies demonstrate that OaIseQM requires the substrate-binding protein (OaIseP) and a Na+ gradient to drive transport. Modeling of the OaIsePQM complex supports that elevator-type conformational changes are involved in this unique coupled transport process. This work expands our knowledge of the transport of organosulfur compounds in bacteria and establishes OaIsePQM as a new model system for exploring the mechanism of TRAP transporters.