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| Paediatric or syndromic cardiomyopathy v7.98 | KLHL24 | Ida Ertmanska Tag Q3_25_promote_green was removed from gene: KLHL24. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.98 | KLHL24 | Ida Ertmanska reviewed gene: KLHL24: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.97 | KLHL24 |
Ida Ertmanska Source NHS GMS was added to KLHL24. Source Expert Review Green was added to KLHL24. Rating Changed from Amber List (moderate evidence) to Green List (high evidence) |
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| Paediatric or syndromic cardiomyopathy v7.60 | KLHL24 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature; to: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. This variant was reported as hot VUS in the publication Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature |
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| Paediatric or syndromic cardiomyopathy v7.60 | KLHL24 | Achchuthan Shanmugasundram Classified gene: KLHL24 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.60 | KLHL24 | Achchuthan Shanmugasundram Added comment: Comment on list classification: There is sufficient evidence available for the association of both monoallelic and biallelic KLHL24 variants with dilated cardiomyopathy/ hypertrophic cardiopmyopathy. Hence, this gene can be promoted to green rating in the next GMS update. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.60 | KLHL24 | Achchuthan Shanmugasundram Gene: klhl24 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.59 | KLHL24 | Achchuthan Shanmugasundram Tag Q3_25_promote_green tag was added to gene: KLHL24. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.59 | KLHL24 | Achchuthan Shanmugasundram Added comment: Comment on phenotypes: OMIM phenotypes accessed on 01 September 2025. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.59 | KLHL24 | Achchuthan Shanmugasundram Phenotypes for gene: KLHL24 were changed from Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.58 | KLHL24 | Achchuthan Shanmugasundram Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.57 | KLHL24 | Achchuthan Shanmugasundram edited their review of gene: KLHL24: Changed publications to: 27889062, 29779254, 30120936, 31649980, 32870709, 35975634, 36672924, 39472908 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Paediatric or syndromic cardiomyopathy v7.57 | KLHL24 |
Achchuthan Shanmugasundram changed review comment from: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature; to: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one paediatric patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature |
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| Paediatric or syndromic cardiomyopathy v7.57 | KLHL24 |
Achchuthan Shanmugasundram gene: KLHL24 was added gene: KLHL24 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature Mode of inheritance for gene: KLHL24 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KLHL24 were set to 27889062; 29779254; 30120936; 31649980; 32870709; 35975634; 36672924; 3947290 Phenotypes for gene: KLHL24 were set to Epidermolysis bullosa simplex 6, generalized intermediate, with or without cardiomyopathy, OMIM:617294; epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, MONDO:0015006; Cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, OMIM:620236; cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, MONDO:0859372 Mode of pathogenicity for gene: KLHL24 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: KLHL24 was set to GREEN Added comment: Monoallelic cases: PMID:30120936 (2019) reported 20 patients from 10 families with monoallelic gain-of-function variants affecting the translation initiation codon of KLHL24 gene (c.1A>G & c.2T>C), of which ten patients have been previously reported in PMID:27889062 (2016). They all had epidermolysis bullosa (EB), which is characterised by cutaneous and mucosal fragility. 17 (85%) of these patients had evidence of cardiac involvement with either elevated cardiac biomarkers or documented dilated cardiomyopathy (DCM) (8/20 patients [40%]), leading to death at an early age in two of them. PMID:29779254 (2018) reported a family of Dutch descent with KLHL24-EBS that was reported with the same translation initiation codon variant c.1A>G. In addition to the cutaneous phenotypes, the affected father also developed a rapidly progressive DCM of unknown aetiology at the age of 18 years for which a cardiac transplantation was necessary within a year of the first clinical signs being seen. PMID:31649980 (2019) reported a 14-year-old female patient with EBS and severe early-onset DCM who presented with heart failure at 14, required LVAD and orthotopic heart transplant. She was also identified with the same start codon variant (c.1A>G). PMID:35975634 (2022) reported a four‐generation Australian family where 14 members suffer(ed) from EBS and five from DCM. Next‐generation sequencing and segregation analysis identified a novel heterozygous variant in KLHL24 (c.22A>T/ p.Arg8Ter) in the proband and several other affected members. Monoallelic variants have been associated with relevant phenotypes in OMIM (MIM #617294) and Gene2Phenotype (with 'moderate' rating on skin panel). Biallelic cases: PMID:30715372 (2019) reported 11 young affected adult patients from two unrelated families with hypertrophic cardiomyopathy (HCM), of which 3 died suddenly and 1 had a cardiac transplant due to heart failure. Homozygous KLHL24 variants were identified in these families using genome-wide linkage analysis and exome sequencing (c.1048G>T/ p.Glu350Ter & c.917G>A/ p.Arg306His). PMID:32870709 (2022) reported two hundred and five unrelated families with childhood-onset cardiomyopathy from Saudi Arabia, from which one patient with HCM was identified with homozygous nonsense variant in KLHL24 gene (c.1161G>A/ p.Trp387Ter) . PMID:36672924 (2023) reported eight unrelated probands of Middle Eastern descent presenting with HCM/DCM, of which one patient presenting with mixed HCM/DCM with LVNC was identified with homozygous p.Arg306His missense variant. PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one patient with hypertrophic cardiomyopathy was identified with homozygous missense variant in KLHL24 gene (c.1376T>C/ p.Ile459Thr) via reanalysis of data from trio genome sequencing. Biallelic variants have been associated with relevant phenotypes in OMIM (MIM #620236) and ClinGen ('moderate' rating for hypertrophic cardiomyopathy (MONDO:0005045) by Hereditary Cardiovascular Disease GCEP). Sources: Literature |
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