Roddy Walsh 🇪🇺 🇺🇦
@roddywalsh.bsky.social
Scientist researching genetics/genomics of heritable heart diseases 🧬🫀 | Liberal extremist | Ex-traveller 🌍 | LFC ⚽️ & Munster 🏉 | He/him
A weekend of 10th anniversaries! Sorry to miss the party for St George's MSc Genomic Medicine. But an amazing meeting for the birthday of the Institute for Cardiomyopathies Heidelberg - great speakers, excellent science and a beautiful location.
October 11, 2025 at 3:34 PM
A weekend of 10th anniversaries! Sorry to miss the party for St George's MSc Genomic Medicine. But an amazing meeting for the birthday of the Institute for Cardiomyopathies Heidelberg - great speakers, excellent science and a beautiful location.
IEVs can co-occur with rare Mendelian pathogenic variants, where they cause a severe phenotype including ⬆️ MACE, or in isolation where they have milder effects (age at diagnosis and wall thickness between genotype-positive and genotype-negative cases).
August 29, 2025 at 4:46 PM
IEVs can co-occur with rare Mendelian pathogenic variants, where they cause a severe phenotype including ⬆️ MACE, or in isolation where they have milder effects (age at diagnosis and wall thickness between genotype-positive and genotype-negative cases).
Comparing >10K HCM cases with ancestry-matched controls, we identified 14 IEVs occurring in 6% of cases. Importantly, in 2/3 of carriers, IEVs were in non-sarcomere genes.
While we focused on Euro-ancestry cases, gnomAD data can highlight variants more prevalent in other populations:
While we focused on Euro-ancestry cases, gnomAD data can highlight variants more prevalent in other populations:
August 29, 2025 at 4:46 PM
Comparing >10K HCM cases with ancestry-matched controls, we identified 14 IEVs occurring in 6% of cases. Importantly, in 2/3 of carriers, IEVs were in non-sarcomere genes.
While we focused on Euro-ancestry cases, gnomAD data can highlight variants more prevalent in other populations:
While we focused on Euro-ancestry cases, gnomAD data can highlight variants more prevalent in other populations:
I was getting a bit irritated by ChatGPT increasingly hallucinating people when asked for peer reviewer suggestions. But I'm not sure its sarcastic response was necessary 😒
March 26, 2025 at 8:21 PM
I was getting a bit irritated by ChatGPT increasingly hallucinating people when asked for peer reviewer suggestions. But I'm not sure its sarcastic response was necessary 😒
Regarding monoallelic variants, we did not see an enrichment in UK Biobank analysis, but did see a nominal association with measures of LV hypertrophy. What explains this? The association is clearer to see in populations with high carrier rate? Or other factors?
www.nature.com/articles/s44...
www.nature.com/articles/s44...
February 14, 2025 at 2:44 PM
Regarding monoallelic variants, we did not see an enrichment in UK Biobank analysis, but did see a nominal association with measures of LV hypertrophy. What explains this? The association is clearer to see in populations with high carrier rate? Or other factors?
www.nature.com/articles/s44...
www.nature.com/articles/s44...
This high prevalence of biallelic cases was partially expected based on carrier data in gnomAD (especially p.Gln247* -> Ashkenazi MAF=0.008), but the authors also describe a novel variant (p.Gln93*) with a high MAF of 0.017 in Libyan Jews.
www.nature.com/articles/s44...
www.nature.com/articles/s44...
February 14, 2025 at 2:44 PM
This high prevalence of biallelic cases was partially expected based on carrier data in gnomAD (especially p.Gln247* -> Ashkenazi MAF=0.008), but the authors also describe a novel variant (p.Gln93*) with a high MAF of 0.017 in Libyan Jews.
www.nature.com/articles/s44...
www.nature.com/articles/s44...
Interesting case study of a homozygous PLN variant (p.L39*) in a patient with severe DCM requiring HTx (het parents had LV hypertrophy). onlinelibrary.wiley.com/doi/10.1111/... Just the third such case reported (AFAIK) - PLN has very complex geno-pheno associations... #cardiogen #cardiosky 🧬
December 16, 2024 at 5:23 PM
Interesting case study of a homozygous PLN variant (p.L39*) in a patient with severe DCM requiring HTx (het parents had LV hypertrophy). onlinelibrary.wiley.com/doi/10.1111/... Just the third such case reported (AFAIK) - PLN has very complex geno-pheno associations... #cardiogen #cardiosky 🧬
A little editorial I wrote for #JACCHF on the challenges of identifying modifier genetic factors for hypertrophic cardiomyopathy. @jaccjournals.bsky.social authors.elsevier.com/a/1kCHM7tD%7... (<- free access link until Jan 21st) #cardiogen
December 2, 2024 at 9:05 PM
A little editorial I wrote for #JACCHF on the challenges of identifying modifier genetic factors for hypertrophic cardiomyopathy. @jaccjournals.bsky.social authors.elsevier.com/a/1kCHM7tD%7... (<- free access link until Jan 21st) #cardiogen
This RE5 variant is found in 4% of Thai BrS cases (case-control OR=45) but absent in >75k non-Thai Asian genomes. Carriers had severe arrhythmic phenotypes, therefore identification and clinical management of carriers is critical to reduce the burden of sudden death in Thailand.
December 21, 2023 at 3:00 PM
This RE5 variant is found in 4% of Thai BrS cases (case-control OR=45) but absent in >75k non-Thai Asian genomes. Carriers had severe arrhythmic phenotypes, therefore identification and clinical management of carriers is critical to reduce the burden of sudden death in Thailand.
To validate its effect, we used CRISPR-Cas9 to introduce the heterozygous variant into hiPSCs. In hiPSC-derived cardiomyocytes, it reduced allele-specific SCN5A expression and caused a 30% reduction in sodium current density based on single cell electrophysiology.
December 21, 2023 at 3:00 PM
To validate its effect, we used CRISPR-Cas9 to introduce the heterozygous variant into hiPSCs. In hiPSC-derived cardiomyocytes, it reduced allele-specific SCN5A expression and caused a 30% reduction in sodium current density based on single cell electrophysiology.
To explore this, we sequenced genomes of BrS cases and controls from Thailand. In a BrS-enriched haplotype at SCN5A/10A locus, a rare non-coding variant in an SCN5A intronic enhancer (RE5) was deemed likely causal – affects a conserved base & disrupts a Mef2 TF binding site.
December 21, 2023 at 2:59 PM
To explore this, we sequenced genomes of BrS cases and controls from Thailand. In a BrS-enriched haplotype at SCN5A/10A locus, a rare non-coding variant in an SCN5A intronic enhancer (RE5) was deemed likely causal – affects a conserved base & disrupts a Mef2 TF binding site.
BrS is several times more prevalent in East/Southeast Asia compared to other regions but relative yield of ultra-rare LoF variants is lower (~5%). An intermediate effect variant, p.Arg965Cys, is found in 6-7% of cases, but other factors underlying this ⬆️ prevalence are unknown.
December 21, 2023 at 2:59 PM
BrS is several times more prevalent in East/Southeast Asia compared to other regions but relative yield of ultra-rare LoF variants is lower (~5%). An intermediate effect variant, p.Arg965Cys, is found in 6-7% of cases, but other factors underlying this ⬆️ prevalence are unknown.
Brugada syndrome (BrS) is a heritable cardiac disease causing sudden death in young adults. LoF coding variants in SCN5A are found in 20% of Euro-ancestry cases and GWAS reveals a strong polygenic component (SNP heritability 0.17-0.34) & several strong loci at SCN5A/10A.
December 21, 2023 at 2:58 PM
Brugada syndrome (BrS) is a heritable cardiac disease causing sudden death in young adults. LoF coding variants in SCN5A are found in 20% of Euro-ancestry cases and GWAS reveals a strong polygenic component (SNP heritability 0.17-0.34) & several strong loci at SCN5A/10A.
The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype - new review article, online now at JCTR, which describes the genetic basis of LVNC and the diagnostic utility of genetic testing. link.springer.com/article/10.1...
November 29, 2023 at 7:08 PM
The Trouble with Trabeculation: How Genetics Can Help to Unravel a Complex and Controversial Phenotype - new review article, online now at JCTR, which describes the genetic basis of LVNC and the diagnostic utility of genetic testing. link.springer.com/article/10.1...
This study highlights the increasing genetic complexity of cardiomyopathies, with many genes likely to represent variations on a semi-dominant mode of inheritance. Understanding the characteristics of each gene-disease relationship is critical for effect clinical application.
October 9, 2023 at 3:57 PM
This study highlights the increasing genetic complexity of cardiomyopathies, with many genes likely to represent variations on a semi-dominant mode of inheritance. Understanding the characteristics of each gene-disease relationship is critical for effect clinical application.
For this reason, we tested the 18 recessive genes identified by the meta-analysis for monoallelic associations with cardiac phenotypes and traits in the UK Biobank and identified several novel associations, e.g. LMOD2 truncating variants with DCM.
October 9, 2023 at 3:57 PM
For this reason, we tested the 18 recessive genes identified by the meta-analysis for monoallelic associations with cardiac phenotypes and traits in the UK Biobank and identified several novel associations, e.g. LMOD2 truncating variants with DCM.
However, discrete categorisation of genes into dominant/recessive is over simplistic, with textbook Mendelian definitions often not reflecting clinical reality, e.g. biallelic variants in sarcomeric HCM/DCM genes lead to complex phenotypes depending on gene and variant class.
October 9, 2023 at 3:56 PM
However, discrete categorisation of genes into dominant/recessive is over simplistic, with textbook Mendelian definitions often not reflecting clinical reality, e.g. biallelic variants in sarcomeric HCM/DCM genes lead to complex phenotypes depending on gene and variant class.
In this study, we performed a meta-analysis of recessive cardiomyopathy reports (triaging >2k papers), identifying 18 genes with robust & replicated association with isolated/primary cardiomyopathy, largely characterised by DCM phenotypes, early disease onset and severe outcomes.
October 9, 2023 at 3:56 PM
In this study, we performed a meta-analysis of recessive cardiomyopathy reports (triaging >2k papers), identifying 18 genes with robust & replicated association with isolated/primary cardiomyopathy, largely characterised by DCM phenotypes, early disease onset and severe outcomes.
Cardiomyopathies are typically inherited in an autosomal dominant manner (when Mendelian-like variants are identified). However, while the number of dominant gene associations has plateaued in recent years, there have been increasing numbers of reported recessive genes.
October 9, 2023 at 3:55 PM
Cardiomyopathies are typically inherited in an autosomal dominant manner (when Mendelian-like variants are identified). However, while the number of dominant gene associations has plateaued in recent years, there have been increasing numbers of reported recessive genes.