Extensive identification of genes involved in congenital and structural heart disorders and cardiomyopathy

Abstract

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, with their human orthologs being categorized as VUR. Using UK Biobank data, we validate the importance of the DNAJC18 gene for cardiac homeostasis by showing that its loss of function is associated with altered left ventricular systolic function. Our results identify hundreds of previously unappreciated genes with potential function in congenital heart disease and suggest causal function of five VUR in congenital heart disease.

RBPMS2 Is a Myocardial-Enriched Splicing Regulator Required for Cardiac Function

“… 104 To our knowledge, the developmental expression pattern of Rbpms2 has not been published, 37 but Rbpms2 knockout mice did not show cardiac defects at 12 weeks of age. 105 Taken together, these data suggest that rbpms2 serves an indispensable function in the zebrafish heart, whereas Rbpms performs a similarly important function in the mouse heart. It remains possible that Rbpms2 and Rbpms perform semiredundant functions in the mouse heart, which would be revealed if the cardiac phenotype of Rbpms, Rbpms2 double mutant mice were more severe than Rbpms -null animals.…”

Early-stage idiopathic Parkinson’s disease is associated with reduced circular RNA expression

“…We identified altered expression of circRNAs (derived from DOP1B and INTS6L ), whose host genes have not been functionally linked to PD (Supplementary Data 9 ). However, copy number variation in DOP1B has previously been linked to Alzheimer’s disease 109 , while deletion of INTS6L leads to a cardiomyopathic phenotype 110 . Nonetheless, our data extend the growing body of evidence linking circRNA dysregulation to PD 60 .…”

Knockout mice are an important tool for human monogenic heart disease studies

“…The highly standardised high-throughput screening pipelines such as the IMPC contribute to generating a high volume of data and provide mouse models that can assist the prioritisation and validation of variants found in those genes. The identification of genes, mutations, and their mechanisms of action that cause and/or contribute to congenital heart disease in humans is far from complete, and alternative approaches for novel disease-gene discovery can benefit from this genotype–phenotype knowledge base ( Spielmann et al, 2022 ).…”

“…It is not always straightforward to assess whether a statistically significant abnormal phenotype, i.e. some deviation from normal morphology, physiology or behaviour ( Robinson and Webber, 2014 ), detected in knockout mice will be observed when loss-of-function (LoF) mutations for the orthologue gene occur in humans ( Spielmann et al, 2022 ). Conversely, knockout mice do not necessarily replicate the phenotypes observed in humans due to potential differences in biology, genetic background or alternative pathways; some of these limitations in mouse models have previously been discussed ( Pound and Ritskes-Hoitinga, 2018 ; Elsea and Lucas, 2002 ).…”