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Paediatric or syndromic cardiomyopathy v7.91 MT-ND5 Achchuthan Shanmugasundram changed review comment from: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the while mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.; to: PMID:14520659 - Three unrelated patients with Leigh's syndrome were identified with m.13513G>A variant in MT-ND5 gene, of which one patient was reported with hypertrophic cardiomyopathy (HCM) among other clinical presentations.

PMID:22759514 - A 3-generation family of Han Chinese descent was reported with maternally inherited isolated HCM. They were identified with a homoplasmic m.12338T>C variant in MT-ND5 gene, leading to the replacement of initiation methionine residue to Threonine, resulting in shortening of the ND5 polypeptide by 2 amino acids.

PMID:23847141 - This study analysed the mitochondrial DNA sequences of a cohort of 743 patients suspected of manifesting a mitochondrial disease. Nine patients were detected with a variant in MT-ND5 gene, and they presented with different combinations of phenotypes. One of four patients with m.13513G>A variants had HCM as one of the clinical features.

PMID:30587702 - A 21-year-old proband presented with biventricular hypertrophy, hyperlactacidemia, pulmonary hypertension, and decreased exercise tolerance. Skeletal muscle biopsy showed features consistent with mitochondrial myopathy. The family was identified with c.1315A>G (p.Thr439Ala) variant in MT-ND5 gene.
Paediatric or syndromic cardiomyopathy v7.81 SELENON Achchuthan Shanmugasundram changed review comment from: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.
Sources: Literature; to: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.

This gene has been associated with Congenital myopathy 3 with rigid spine in OMIM (MIM #602771, OMIM accessed on 06 September 2025) and with SELENON-related myopathy in Gene2Phenotype (with 'definitive' rating).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.81 SELENON Achchuthan Shanmugasundram gene: SELENON was added
gene: SELENON was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: SELENON was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SELENON were set to 35868898
Review for gene: SELENON was set to RED
Added comment: PMID:35868898 (2022) reviewed cases with cardiac involvement in SELENON-related myopathy, where cardiac abnormality was described in 15% of cases (29). The most frequently reported abnormality was pulmonary hypertension (16 patients), of whom eight patients were reported to have right ventricular (RV) dysfunction or increase of RV systolic pressure secondary to respiratory failure and three patients concomitant respiratory insufficiency, of whom two patients died of secondary cardiac failure within several years. Primary left ventricular (LV) dysfunction, including dilated cardiomyopathy (DCM) and decreased LV contractility, was only described in two patients. The first patient had a positive family history for idiopathic cardiomyopathy but not for SELENON-RM, and developed DCM at age of 42 years. No other cause of decreased LV contractility had been documented at paediatric age for the second patient.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult male patient with unspecified cardiomyopathy was identified with a homozygous missense variant (p.Gly315Ser) in SELENON gene via analysis of data from singleton genome sequencing.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the UK 100,000 genomes project cohort, of which one adult patient with unspecified cardiomyopathy was identified with an intragenic homozygous deletion in TANGO2 gene via analysis of data from trio genome sequencing.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.73 TANGO2 Achchuthan Shanmugasundram changed review comment from: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature; to: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. These patients were reported with either homozygous or compound heterozygous variants including small variants and intragenic deletions in TANGO2 gene. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.71 TANGO2 Achchuthan Shanmugasundram gene: TANGO2 was added
gene: TANGO2 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: TANGO2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TANGO2 were set to 26805781; 30245509; 31339582; 32527145; 35568137; 40156300
Phenotypes for gene: TANGO2 were set to Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, OMIM:616878; recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome, MONDO:0018820
Review for gene: TANGO2 was set to GREEN
Added comment: PMID:26805781 (2016) reported the identification of biallelic variants (a missense variant and two different intragenic deletions) in 12 patients from nine unrelated families with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. Hypertrophic cardiomyopathy was reported in a patient from a family with three affected patients (with homozygous exons 3-9 deletion).

PMID:30245509 (2018) reported the identification of biallelic TANGO2 variants (five different variants including the previously described exon 3-9 intragenic deletion in either homozygous or compound heterozygous states) in 14 individuals from 11 unrelated families with a complex clinical phenotype including primarily neurological presentations. Dilated cardiomyopathy was reported in two patients from a family (compound heterozygous for p.Arg32Ter & p.Arg26Lys variants) and left ventricular hypertrophy was reported in one of three patients from family 1 (with 3C>G and exons-3-9 deletion).

PMID:31339582 (2020) reported nine patients from seven unrelated families with biallelic TANGO2 variants (exons 3-9 deletion and small variants). One unrelated patient (subject 5) that harboured a hemizygous deletion of exons 3-9 (second variant was not identified) was reported with hypertrophic cardiomyopathy.

PMID:32527145 (2020) reported a 6-year-old female patient atypical cardiomyopathy, who was identified to harbour a hemizygous deletion of exons 3-9 in the TANGO2 gene via next-generation sequencing.

PMID:35568137 (2022) conducted a retrospective multicentre chart review of TANGO2 deficiency disorder patients admitted with cardiac crises, where 27 children were admitted for 43 cardiac crises at 14 centres. Arrhythmias included ventricular tachycardia in 21 (78%), supraventricular tachycardia in 3 (11%), and heart block in 1 (4%). Nineteen patients (70%) developed cardiomyopathy, and 20 (74%) experienced a cardiac arrest.

PMID:40156300 (2025) reported two unrelated patients with biallelic TANGO2 pathogenic variants (homozygous deletion of exons 4-6 in one and c.605+1G>A in the other). Both patients developed ventricular tachyarrhythmias, and the echocardiogram showed cardiomyopathy.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.64 TKFC Achchuthan Shanmugasundram gene: TKFC was added
gene: TKFC was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
watchlist tags were added to gene: TKFC.
Mode of inheritance for gene: TKFC was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TKFC were set to 32004446; 39251934; 39472908
Phenotypes for gene: TKFC were set to Triokinase and FMN cyclase deficiency syndrome, OMIM:618805; triokinase and FMN cyclase deficiency syndrome, MONDO:0032927; cardiomyopathy, MONDO:0004994
Review for gene: TKFC was set to AMBER
Added comment: PMID:32004446 (2020) reported four affected individuals from 2 consanguineous families with congenital cataracts, developmental delay, liver dysfunction and microcytic anaemia. One of the infants also had fatal dilated cardiomyopathy (DCM) and lactic acidosis following a febrile illness. Both families were identified with homozygous missense variants in TKFC gene, and c.1628G>T (p.Arg543Ile) variant was present in the infant with DCM.

PMID:39251934 (2024) reported two deceased neonate siblings presenting with oculocutaneous albinism type1 (OCA1). They had severe skeletal abnormalities and fatal hypertrophic cardiomyopathy (HCM). Upon performing WES and segregation analysis, positive co-segregation of nonsense homozygous c.346C > T (p.Arg116Ter) variant in TYR gene and missense homozygous c.598G > A (p.Val200Ile) variant in TKFC gene were identified in the two affected patients.

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 DCM was identified with homozygous missense variant in TKFC gene (c.1628G>T/ p.Arg543Ile) via reanalysis of data from trio genome sequencing. This variant is reported as likely pathogenic and the publication states that the phenotype is explained by the genotype.

This gene has been associated with Triokinase and FMN cyclase deficiency syndrome (MIM #618805) in OMIM (phenotype accessed in OMIM on 01 September 2025), which includes DCM as one of the clinical manifestations.
Sources: Literature
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
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
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
Paediatric or syndromic cardiomyopathy v7.38 MTO1 Achchuthan Shanmugasundram gene: MTO1 was added
gene: MTO1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: MTO1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MTO1 were set to 22608499; 23929671; 34547275; 34990597; 39472908
Phenotypes for gene: MTO1 were set to Combined oxidative phosphorylation deficiency 10, OMIM:614702; mitochondrial hypertrophic cardiomyopathy with lactic acidosis due to MTO1 deficiency, MONDO:0013865
Review for gene: MTO1 was set to GREEN
Added comment: PMID:22608499 (2012) reported two infant siblings and an unrelated child of Italian descent with hypertrophic cardiomyopathy and neonatal lactic acidosis. The siblings died early in their life (when 19 days and 40 days old). The affected siblings were identified with compound heterozygous variants in MTO1 gene – a maternal frameshift variant (c.1858dup/ p.Arg620Lysfs(∗)8) and a paternal missense variant (c.1282G>A/ p.Ala428Thr). The unrelated patient was homozygous for the same missense variant (c.1282G>A).

PMID:23929671 (2013) reported five additional patients from three unrelated families, who also presented with hypertrophic cardiomyopathy and lactic acidosis, in addition to other variable phenotypes including psychomotor delay, hypotonia, feeding difficulties and respiratory illness. The two sibling pairs were identified with homozygous missense variants (c.1232C>T/ p.Thr411Ile), while the unrelated patient was reported with compound heterozygous missense variants (c.1402G>A/ p.Ala428Thr & c.1430G>A/ p.Arg477His).

PMID:34547275 (2021) reported the identification of compound heterozygous variants in MTO1 gene in a Chinese patient with complex oxidative phosphorylation deficiency type 10 (COXPD10). This patient had lactic acidosis and cardia abnormalities such as myocarditis and tachycardia, but not hypertrophic cardiomyopathy. The identified variants are c.344delA (p.Asn115Thrfs*11, frameshift) and c.1055C>T (p.Thr352Met, missense).

PMID:34990597 (2022) reported a patient with COXPD10 presenting with multiple organ failure, severe pneumonia, sepsis, hyperlactatemia, metabolic acidosis, and moderate anaemia. The patient was identified with compound heterozygous variants in MTO1 gene (c.1291C > T/ p.Arg431Trp and c.1390C > T/ p.Arg464Cys). The patient also showed HCM. This study also reviewed previously published cases of confirmed MTO1 deficiency. Of 42 total cases including the patient reported in this study, 32 patients were reported with HCM and one additional patient was reported with dilated cardiomyopathy.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient with unspecified cardiomyopathy was identified with compound heterozygous missense variants in MTO1 gene (c.938G>C/ p.Arg313Pro & c.1232C>T/ p.Thr411Ile).

There is also functional evidence available in support of the disease association.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.37 NEB Achchuthan Shanmugasundram Added comment: Comment on list classification: There is only patient reported in a large cohort study (UK 100,000 genomes project) with unspecified cardiomyopathy and homozygous NEB variant. No further phenotypic information was reported in the publication (PMID:39472908).

All other reported cases did not have confirmed cardiomyopathy (despite some cardiac involvement in a few cases) or had Nemaline myopathy and cardiomyopathy with variants in other genes (e.g. ACTA1).

There is no functional evidence to suggest the association of NEB with cardiomyopathy.

Hence, this gene should be rated red.
Paediatric or syndromic cardiomyopathy v7.34 PLD1 Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.; to: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
Paediatric or syndromic cardiomyopathy v7.34 SGCG Achchuthan Shanmugasundram changed review comment from: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.; to: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

There is also functional evidence from mice model, which supports the association of SGCG gene with cardiomyopathy.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram changed review comment from: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).
Sources: Literature; to: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).

PMID:14991064 provided functional evidence from Sgcg knockout mice, which develop a progressive cardiomyopathy characterised by focal myocardial degeneration and fibrosis. Transgenic rescue experiments in mice showed that re-expressing SGCG only in cardiac muscle (but not in vascular muscle) was sufficient to prevent the cardiomyopathy in Sgcg-null mice.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.33 SGCG Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with biallelic SGCG variants and with 'Muscular dystrophy, limb-girdle, autosomal recessive 5' (MIM #253700). However, the disease has a variable presentation and cardiomyopathy was reported only in a subset of patients. Five different variants (two frameshift and three missense variants) were identified in these patients with cardiac phenotypes, including the p.Cys283Tyr founder variant in Gypsies.

As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.31 SGCG Achchuthan Shanmugasundram gene: SGCG was added
gene: SGCG was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: SGCG was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: SGCG were set to 10942431; 11053682; 24464767; 39472908
Phenotypes for gene: SGCG were set to Muscular dystrophy, limb-girdle, autosomal recessive 5, OMIM:253700; autosomal recessive limb-girdle muscular dystrophy type 2C, MONDO:0009677
Review for gene: SGCG was set to GREEN
Added comment: PMID:10942431 (2000) reported two siblings of Middle Eastern descent with autosomal recessive limb-girdle muscular dystrophy (LGMDR5), of which one of them presented with dilated cardiomyopathy. Both siblings were identified with a homozygous frameshift variant in SGCG gene (c.525delT).

PMID:11053682 (2000) reported a homogeneous group of 10 gypsy patients from three kindreds with a homozygous founder variant (c.848G>A/ p.Cys283Tyr) in SGCG gene. While all 10 had severe limb-girdle muscular dystrophy, right ventricle free wall hypertrophy and/or dilatation was found in six of these patients, and four of the older patients had early signs of right ventricular dysfunction.

PMID:24464767 (2014) reported the retrospective analysis of 19 patients, of which 11 patients were reported with SGCG-related LGMDR5 and 8 were reported with SGCA-related LGMDR3. All but one patient with gamma-sarcoglycanopathy harboured c.525delT variant, and one patient had c.525delT variant. Five of these 11 patients with LGMDR5 had left ventricular dysfunction (LVEF < 50%).

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient with dilated cardiomyopathy was identified with compound heterozygous missense variants in SGCG gene (c.158T>C/ p.Leu53Pro & c.787G>A/ p.Glu263Lys), of which c.787G>A variant was proven to be inherited.

This gene has been associated with Muscular dystrophy, limb-girdle, autosomal recessive 5 (MIM #253700) in OMIM, which also records cardiac involvement in a subset of patients as relevant clinical presentation (abnormal precordial tall R waves on EKG, right ventricular hypertrophy and right ventricular dilatation).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.30 PLD1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There is an additional patient reported with dilated cardiomyopathy and homozygous splice donor variant in PLD1 gene from the UK 100,000 genomes project cohort.

As previously reviewed by Jesse Hayesmoore and agreed by the NHS Genomic Medicine Service, this gene has recently been demoted from green rating. This was because the variants previously identified from patients might not be pathogenic for a severe autosomal recessive condition, as they are frequently present in homozygous state in general populations. Hence, the rating for this gene should remain amber despite the report of this additional case.
Paediatric or syndromic cardiomyopathy v7.23 NAXD Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >10 unrelated patients reported with biallelic NAXD variants and with 'Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2' (MIM #618321). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.21 NAXD Achchuthan Shanmugasundram gene: NAXD was added
gene: NAXD was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NAXD were set to 30576410; 32462209; 39472908; 39822994
Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2, OMIM:618321; NAD(P)HX dehydratase deficiency, MONDO:0034121
Review for gene: NAXD was set to GREEN
Added comment: PMID:30576410 (2019) reported six unrelated individuals with biallelic NAXD variants, and with encephalopathy precipitated by febrile illnesses. They all had severe neurological deterioration and died in early childhood. One of these six patients, who is a girl of Indian descent developed dilated cardiomyopathy and heart failure, and was identified with homozygous c.54_57delAAGA (p.Ala20Phefs*9) variant.

PMID: 32462209 (2020) reported a seven-year-old male patient that experienced rapid deterioration and after gastroenteritis and died suddenly. An autopsy imaging CT scan showed thickening of the myocardial wall and gross hypertrophic cardiomyopathy in the patient. His paternal uncle also died due to acute myocardial infarction at the age of 28. Biallelic variants (c.44delG/ p.Arg15Glnfs*3 & c.54_57delAAGA/ p.Ala20Phefs*9) were identified by WES in the patient and these variants are present in heterozygous state in the parents.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one female patient with dilated cardiomyopathy was identified with homozygous variant in NAXD gene (c.54_57del/ p.Ala20PhefsTer9).

PMID:39822994 (2024) reported a 47-month-old male patient of Chinese descent that experienced a sharp deterioration after febrile illness, causing heart failure, cardiogenic shock, and ultimately death. This patient was diagnosed with myocarditis and dilated cardiomyopathy and was identified with compound heterozygous variants in NAXD gene (c.43C>T/ p.Arg15Ter & c.781G>T/ p.Gly261Cys).

This gene has been associated with MIM #618321 in OMIM, which mentions cardiomyopathy as one of the clinical presentations that is observed in some patients.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.20 AIFM1 Achchuthan Shanmugasundram Added comment: Comment on list classification: There are >20 unrelated patients reported with hemizygous AIFM1 variants and with Combined oxidative phosphorylation deficiency 6 (MIM #300816). However, the disease has a variable presentation and cardiomyopathy was reported in four unrelated patients. As this panel includes syndromic cases, this gene can be considered for promotion to green rating in the next GMS update.
Paediatric or syndromic cardiomyopathy v7.18 AIFM1 Achchuthan Shanmugasundram gene: AIFM1 was added
gene: AIFM1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: AIFM1 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: AIFM1 were set to 22019070; 28967629; 34117073; 39472908
Phenotypes for gene: AIFM1 were set to Combined oxidative phosphorylation deficiency 6, OMIM:300816
Review for gene: AIFM1 was set to GREEN
Added comment: PMID:22019070 (2011) reported three siblings of Palestinian descent with early prenatal verntriculomegaly, of which two brothers were investigated further. The two brothers presented with infantile encephalomyopathy. One of them died at the age of 4 years due to cardiac failure secondary to aspiration pneumonia, and the other died at 3 months of age because of hypertrophic cardiomyopathy and aspiration pneumonia. Using linkage analysis in the family, followed by whole exome sequencing, a pathogenic variant in the AIFM1 gene was identified in patient B (c.923G > A/ p.Gly308Glu), which segregated with the disease state and was absent in 86 anonymous controls.

PMID:28967629 (2018) reported two unrelated male patients with AIFM1 variants and they displayed distinct phenotypes including progressive ataxia which partially improved with riboflavin treatment. Cardiomyopathy was only reported in patient 2, who also displayed severe limb and palatal myoclonus, followed by ataxia, cerebellar atrophy, ophthalmoplegia, sensorineural hearing loss, and hyporeflexia. The c.422C > T (p.Thr141Ile) hemizygous variant was identified in this patient via WES and validated by Sanger sequencing and was confirmed de novo.

PMID:34117073 (2021) reported three affected males (proband, brother and maternal uncle) exhibiting severe multisystem pathology, metabolic acidosis, and early demise. Biventricular hypertrophy was observed via foetal heart echocardiogram in the proband, and by limited autopsy in the maternal uncle. A missense hemizygous AIFM1 variant (c.506C > T/ p.Pro169Leu) was identified in the proband and sibling and this variant is absent in reference population databases, as discussed in this publication.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one male patient was identified with hemizygous variant in AIFM1 gene (c.603_605del/ p.Arg201del?).

This gene is associated with Combined oxidative phosphorylation deficiency 6 (MIM #300816) in OMIM, which includes hypertrophic cardiomyopathy as one of the variable clinical presentations.
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.17 FBXL4 Achchuthan Shanmugasundram changed review comment from: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature; to: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter).

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.16 FBXL4 Achchuthan Shanmugasundram gene: FBXL4 was added
gene: FBXL4 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: FBXL4 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: FBXL4 were set to 23993193; 23993194; 25868664; 26404457; 28940506; 38359748; 39472908
Phenotypes for gene: FBXL4 were set to Mitochondrial DNA depletion syndrome 13 (encephalomyopathic type), OMIM:615471
Review for gene: FBXL4 was set to GREEN
Added comment: PMID:23993193 (2013) reported three consanguineous families of Arab descent with homozygous FBXL4 loss-of-function mutations causing a lethal neonatal encephalopathy. The proband from family 2 presented in the first month of life with severe hypotonia, encephalopathy, cardiomyopathy, and lactic acidosis, leading to death at age 4 months. Three older siblings presented with a similar fatal, early-onset phenotype, and the proband’s mother has also suffered three miscarriages. Exome sequencing identified nonsense variant in FBXL4 (c.1303C>T/ p.(Arg435Ter)), predicting an earlier truncation of the protein than that observed in family 1.

PMID:23993194 (2013) reported nine patients from seven unrelated families with FBXL4 variants causing early-onset mitochondrial encephalomyopathy. Two of these patients were reported with cardiac phenotypes: Prenatal ultrasound revealing growth retardation and dilated lateral ventricles in patient S7 (of Bahrain Arab descent) and echocardiography revealing left ventricular heart hypertrophy in patient S8 (of European descent). Patient S7 harboured homozygous missense variant (c.1652T>A/ p.(Ile551Asn)), while patient S8 harboured compound heterozygous variants – a nonsense and a missense variant in FBXL4 gene (c.614T>C; c.106A>T/ p.(Ile205Thr); p.(Arg36Ter].

PMID:25868664 (2015) reported 21 individuals from 19 different families of various ethnic backgrounds with biallelic FBXL4 variants and early-onset encephalopathic mitochondrial DNA depletion syndrome, of which three cases were previously reported in PMID:23993194 and one case was reported in PMID:23993193. Cardiac disease was observed at first presentation in seven individuals and evolved in another patient during the course and these patients included one from PMID:23993194. Cardiomyopathy (non-progressive or hypertrophic) was reported in four of these patients, while one other patient was reported with Borderline left-ventricular hypertrophy and hyperdynamic left ventricular function.

PMID:26404457 (2016) reported a female neonate born to a French-Canadian mother with severe multisystem disease including lactic acidosis, cystic white matter lesions, cardiomyopathy, arrhythmias, and immunodeficiency. This patient was identified with homozygous frameshift variant in FBXL4 gene (c.1641_1642delTG; c.141del/ p.(Cys547Ter); p.(Asn48MetfsTer4)).

PMID:28940506 (2017) reported 37 unreported individuals and 11 previously unreported pathogenic variants in addition to review of 36 FBXL4 variants from 50 affected individuals with a total of 87 patients and 47 variants. Hypertrophic cardiomyopathy, congenital heart disease and arrhythmia were reported in 20% (15/74), 19% (14/74) and 12% (9/78) patients respectively.

PMID:39472908 (2024) reported paediatric and adult probands with diverse cardiomyopathies from the 100,000 genomes project, of which one patient was identified with compound heterozygous variants in FBXL4 variants (c.1641_1642del/ p.Cys547Ter

There is also functional evidence available from mice model, where transfection of FBXL4 rescued the cardiac geometry and the mitochondrial integrity with altered mitochondrial dynamics in the adult mice model of the heart failure with preserved ejection fraction (PMID: 38359748).
Sources: Literature
Paediatric or syndromic cardiomyopathy v7.15 FLII Achchuthan Shanmugasundram changed review comment from: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian decent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys).

PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch decent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp).

Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation.

This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).; to: PMID:32870709 (2020) reported a large cohort of 205 unrelated patients with various forms of childhood-onset cardiomyopathy (CM), in which two unrelated patients of Saudi Arabian descent with infantile-onset dilated CM were identified with homozygous missense variants (p.Leu674Val & p.Arg1240Cys).

PMID:37561591 (2023) identified biallelic variants in FLII gene in three unrelated families with idiopathic, early-onset dilated CM of which two patients were the ones that were already reported in PMID:32870709. The third patient was a girl of Dutch descent that had onset of CM at around 2 months of age. This patient was identified with compound heterozygous variants (p.Gln454Ter & p.Arg1168Trp).

Introduction of patient-specific FLII variants into the zebrafish genome using CRISPR/Cas9 genome editing resulted in the manifestation of key aspects of morphological and functional abnormalities of the heart, as observed in the patients. In addition, functional studies also provided insights into the function of Flii during ventricular chamber morphogenesis that involves myocardial cell adhesion and myofibril organisation.

This gene has been associated with dilated CM phenotype in OMIM (MIM #620635).
Paediatric or syndromic cardiomyopathy v6.5 ASNA1 Dmitrijs Rots gene: ASNA1 was added
gene: ASNA1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: ASNA1 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: ASNA1 were set to PMID: 31461301
Phenotypes for gene: ASNA1 were set to Rapidly Progressive Pediatric Cardiomyopathy
Review for gene: ASNA1 was set to AMBER
Added comment: 3 families with functional evidence described in PMID: 31461301
Sources: Literature
Paediatric or syndromic cardiomyopathy v6.5 MYZAP Eleanor Williams commented on gene: MYZAP: Copied this gene from R132 Dilated and arrhythmogenic cardiomyopathy since NHS GMS reviewers suggest that it is more suited to be on the R135 Paediatric or syndromic cardiomyopathy panel.

Note the MYZAP gene is part of the GRINL1A complex transcription unit, or GCOM1 gene, which also includes the downstream POLR2M gene.

Helio et al. (2021) (PMID: 34899865) - 2 Finnish families with different homozygous variants in GCOM1 in affected individuals. Probands had either DCM or arrhythmogenic right ventricular cardiomyopathy (ARVC). Note in Family 1, one family member without the variant had DCM secondary to lymphocytic myocarditis. Age at diagnosis ranged from 24 to 41.

Maver et al. (2022) (PMID: 35840178) - 2 Slovenian brothers affected by severe DCM with onset at ages 14 and 16 years. Both had a homozygous premature termination variant in MYZAP.

Ochoa et al. (2024) (PMID: 38436102) - 2 sisters of Spanish ancestry with compound heterozygous variants in MYZAP and a severe form of DCM. Neither patient had extracardiac features. Both were diagnosed in their early 30s.
Paediatric or syndromic cardiomyopathy v5.7 TAF1A Sarah Leigh edited their review of gene: TAF1A: Added comment: Biallelic TAF1A variants have been associated with dilated cardiomyopathy. To date, five missense TAF1A variants and a 1.62Mb deletion (that includes the TAF1A gene) have been reported in three unrelated cases of childhood dilated cardiomyopathy (PMIDs 28472305; 29367541; 37501913, personal communication from Genomics Clinical Fellow). The unaffected parents of these cases were all heterozygous for the relevant TAF1A variant. A stable knockout of the single taf1a zebrafish homolog, was used to generate homozygous embryos, which mirrored the heart failure phenotype beginning at 6 days post-fertilization (PMID: 28472305).; Changed rating: GREEN; Changed mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Paediatric or syndromic cardiomyopathy v3.43 CASZ1 Ludmila Volozonoka gene: CASZ1 was added
gene: CASZ1 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: CASZ1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: CASZ1 were set to 36293425; 31268246; 28099117; 27693370; 37509718
Phenotypes for gene: CASZ1 were set to Pediatric Dilated Cardiomyopathy; Pediatric LVNC
Review for gene: CASZ1 was set to GREEN
Added comment: Loss of Function variants described in patients with pediatric dilated cardiomyopathy, pediatric LVNC (36293425; 31268246). Our laboratory identified the LOF variant in a pediatric patient with LVNC.

The limited implication in congenital ventricular septal defect (27693370) - authors identified a missense variant.

Review article on CASZ1 (37509718).
Sources: Literature
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines. ; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease (not cardiomyopathy) have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.43 PLD1 Jesse Hayesmoore changed review comment from: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign). Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.; to: On the basis of functional data described in PMIDs: 27799408 and 33645542, PLD1 certainly seems to be a plausible functional candidate for causality of cardiac valvular defects. The main paper linking this gene with congenital heart disease / cardiomyopathy is Lahrouchi et al. (2021; PMID: 33645542; note this also includes the same 2 cases as described in Ta-Shma et al. 2017 PMID: 27799408). The paper presents 19 families with severe fetal- / neonatal-onset congenital heart (mainly valvular) defects and 2 with cardiomyopathy where affected babies were homozygous or compound heterozygous for PLD1 variants. The paper also provides some functional analysis of missense variants detected, showing that many but not all of them result significant loss of PLD1 function. Unfortunately, the paper does not include a LOD score, and there is very little cosegregation data presented for any of the variants. In addition, 4 of the 31 variants they promote as pathogenic for autosomal recessive disease are detected in multiple homozygous individuals on gnomAD, which I think provides significant evidence that they might not be pathogenic for a severe autosomal recessive condition. Most notably, 1 of the variants (i.e. I668F), which the authors promote as a pathogenic Ashkenazi Jewish founder variant (but which is also fairly frequent in non-Finnish Europeans) is detected in 7 homozygotes on gnomAD and was found to have ~80% loss of PLD1 function in their assay. This suggests that significant loss of function of this gene (i.e. down to 20%) might not be causative of a severe recessive condition (that is not to say that total or near total loss of function is not causative). Three other of the variants promoted as pathogenic in this article are also detected in homozygotes on gnomAD.

I think one of the major pieces of missing information required to make a full assessment of this gene’s linkage to disease is that is unknown how frequent biallelic (apparently loss of function) variant genotypes are in the general population or in healthy control individuals. Although homozygosity for any one variant can be determined from gnomAD, compound heterozygosity (which is likely to represent the vast majority of biallelic genotypes) cannot be assessed on gnomAD, and I can find no record in the literature of this being assessed in a normal control cohort. Without this information, we cannot know whether biallelic PLD1 genotypes are specific to babies with this severe phenotype. Without knowing this, and in the absence of any significant cosegregation data for any variant, there is no reasonable basis upon which one can conclude that this is a valid autosomal recessive gene for the phenotype. Without such validation, PVS1 cannot be applied for any apparent loss of function variant. Given this, and the general lack of cosegregation data for any one variant, I do not believe there is any PLD1 variant reported in the literature that could be classified as anything but uncertain significance (if not benign or likely benign) on the basis of current variant classification guidelines. Also, there are only two cases of biallelic variants in neonates where the primary phenotype is cardiomyopathy, and of these only one was dilated cardiomyopathy (the other was histiocytoid cardiomyopathy). Hence, the evidence linking this gene to cardiomyopathy is even weaker than it is for valvular defects. I, therefore, do not feel there is sufficient evidence to justify this gene being tested as part of the R135 paediatric cardiomyopathy gene panel.

Other papers (e.g. PMIDs: 33142350, 35380090, 36923242, 37770978) reporting a link between PLD1 genotypes and early onset cardiac disease have been published. However, again, I do not think there is sufficient data in the articles to allow any of the variants detected to be confidently classified as anything but VUS according to current variant classification guidelines.
Paediatric or syndromic cardiomyopathy v3.31 LDB3 Achchuthan Shanmugasundram changed review comment from: As reviewed by Dmitrijs Rots, there are five unrelated cases reported with biallelic LDB3 variants and lethal paediatric dilated cardiomyopathy in PMID:36253531. It was also reported that these biallelic loss-of-function variants lead to an early-onset and more severe phenotype of cardiomyopathy and myopathy.

Monoallelic variants in LDB3 are associated with dilated cardiomyopathy with or without left ventricular noncompaction in both OMIM (MIM #601493) and Gene2Phenotype (with 'limited' rating in the DD panel). Two unrelated families reported in PMID:16427346, of which twin sisters from a family presented with isolated LVNC shortly after the brith, while male proband from second family was diagnosed at 13 years of age. The six unrelated patients with hypertrophic cardiomyopathy were diagnosed in the third to seventh decades of life.; to: As reviewed by Dmitrijs Rots, there are five unrelated cases reported with biallelic LDB3 variants and lethal paediatric dilated cardiomyopathy in PMID:36253531. It was also reported that these biallelic loss-of-function variants lead to an early-onset and more severe phenotype of cardiomyopathy and myopathy.

Monoallelic variants in LDB3 are associated with dilated cardiomyopathy with or without left ventricular noncompaction in both OMIM (MIM #601493) and Gene2Phenotype (with 'limited' rating in the DD panel). Two unrelated families reported in PMID:16427346, of which twin sisters from a family presented with isolated LVNC shortly after the brith, while male proband from second family was diagnosed at 13 years of age. The six unrelated patients with hypertrophic cardiomyopathy were diagnosed in the third to seventh decades of life (PMID:17097056).
Paediatric or syndromic cardiomyopathy v3.19 NAA10 Achchuthan Shanmugasundram gene: NAA10 was added
gene: NAA10 was added to Paediatric or syndromic cardiomyopathy. Sources: Literature
Mode of inheritance for gene: NAA10 was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females
Publications for gene: NAA10 were set to 29748569
Phenotypes for gene: NAA10 were set to Ogden syndrome, OMIM:300855
Review for gene: NAA10 was set to AMBER
Added comment: PMID:29748569 reported the identification of previously undescribed NAA10 variant (c.215T>C; p.Ile72Thr) in three boys from two unrelated families with a milder phenotypic spectrum in comparison to most of the previously described patients with NAA10 variants. These boys had developmental delay, intellectual disability, and hypertrophic cardiomyopathy.

This gene has been associated with Ogden syndrome in both OMIM ands Gene2Phenotype and the OMIM record includes hypertrophic cardiomyopathy and other cardiac abnormalities as clinical manifestations of this disorder.
Sources: Literature
Paediatric or syndromic cardiomyopathy v3.1 TBX20 Matthew Edwards gene: TBX20 was added
gene: TBX20 was added to Paediatric or syndromic cardiomyopathy. Sources: Other
Mode of inheritance for gene: TBX20 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Publications for gene: TBX20 were set to PMID: 33585493; PMID: 275101702, PMID: 28798025; PMID: 32600061, PMID: 22080862
Phenotypes for gene: TBX20 were set to Cardiomyopathy, dilated with or without LVNC; Atrial septal defect, congential heart disease
Penetrance for gene: TBX20 were set to unknown
Review for gene: TBX20 was set to GREEN
Added comment: TBX20 encodes transcription factors involved in the regulation of several important aspects of cardiac development and homeostasis and heart function. Pathogenic variants in TBX20 are widely associated with the complex spectrum of congenital heart defects and it has also been reported in association with dilated cardiomyopathies and heart arrhythmia (PMID: 33585493)
Although loss of function (LoF) has not been clearly established as a disease mechanism for TBX20 in dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC), several LoF alterations have been reported in individuals with these conditions, segregating with disease in several families (PMID: 275101702, PMID: 28798025). In addition mouse model studies have shown that mutant mice with conditional Tbx20 ablation in adult cardiomyocytes have dilated hearts with a rapid loss of systolic function and slower conduction and severe arrhythmia (PMID: 32600061, PMID: 22080862). A functional study ofa truncating variant identified in a DCM case, revealed that the truncated TBX20 protein had no transcriptional activity in contrast to its wild-type counterpart, which further supports the previous mouse model findings and LoF as a disease mechanism for DCM/LVNC (PMID: 275101702).
Sources: Other
Paediatric or syndromic cardiomyopathy v1.55 RNF220 Ivone Leong changed review comment from: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association; however, the ID severity in these patients do not meet the criteria (moderate to severe) for this panel (patients show mild (mostly) to moderate severity). Therefore, this gene has been given an Amber rating.; to: Comment on list classification: New gene added by Konstantinos Varvagiannis. This gene is currently not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 cases for this gene; however, 3 of the cases described in PMID:33964137 are of Roma descent and haplotype analysis has shown that the variant found in these families are due to a founder effect (c.1094G>A, p.Arg365Gly). A separate Roma family also has the same variant (c.1094G>A, p.Arg365Gly). An Italian family with similar phenotypes has a different variant (c.1088G>A, p.Arg363Gly). The authors also report on in vitro and in vivo studies.

There is enough evidence to support a gene-disease association. Therefore, this gene should be Green at the next review.
Paediatric or syndromic cardiomyopathy v1.53 KIF20A Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a phenotype in OMIM but not in Gene2Phenotype. PMID: 29357359 describes 1 family with 2 affect sibs. The authors also made a zebrafish MO model, which had a progressive cardiac phenotype starting at 48 hpf. Currently, there is insufficient evidence to support a gene-disease association. Therefore this gene has been given a Red rating.
Paediatric or syndromic cardiomyopathy v1.38 NRAP Ivone Leong gene: NRAP was added
gene: NRAP was added to Cardiomyopathies - including childhood onset. Sources: Literature
Q2_21_rating tags were added to gene: NRAP.
Mode of inheritance for gene: NRAP was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: NRAP were set to 30384889; 33534821; 28611399; https://doi.org/10.1101/2020.10.12.20211474; 32870709
Phenotypes for gene: NRAP were set to Dilated cardiomyopathy, MONDO:0005021 Edit
Review for gene: NRAP was set to GREEN
Added comment: This gene is Green on the Dilated cardiomyopathy - adult and teen (Version 1.22) with the following reviews:

"This gene is not associated with a phenotype in OMIM or Gene2Phenotype. There are >3 unrelated cases of patients with variants in this gene and having DCM. https://doi.org/10.1101/2020.10.12.20211474 also describes a CRISPR knockout zebrafish which had a cardiac phenotype. Therefore, there is enough evidence to support a gene-disease association and this gene is recommended to be promoted Green at the next panel review. Sources: Literature
Ivone Leong (Genomics England Curator), 25 Feb 2021"

"Twenty unrelated families reported with childhood onset DCM. May be more appropriate for the paediatric cardiomyopathy panel."

As affected individuals have childhood onset DCM it was deemed appropriate to add this gene to this panel as well.
Sources: Literature
Paediatric or syndromic cardiomyopathy v1.35 MYLK3 Ivone Leong Added comment: Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is not associated with a phenotype on OMIM or Gene2Phenotype.

PMID: 29235529 describes 2 families with heterozygous variant in this gene. Family A - 2 sibs diagnosed with DCM at 9 and 10 months of age and affected mother diagnosed with DCM at 40 yo. As the children had a more severe phenotype and earlier onset than the mother the authors did further analysis and found the sibs had an additional variant in FLNC, which is also linked to DCM. The authors suggest this additional variant could account for the more severe phenotype in the children.

Family B - 2 brothers diagnosed with DCM at 56 and 52 yo, both have a heterozygous frameshift variant in this gene. Mother and sister had died young and DCM diagnosis is inconclusive.

PMID: 30690923 describes another case. Proband has a heterozygous frameshift variant in this gene. Rest of the family have no cardiac phenotype and no variants in this gene except for one daughter. Daughter has the same variant and has dilation of LV and ST-T abnormalities but these do not meet the criteria for DCM.

PMID: 32870709 describes three consanguineous families with homozygous variants in this gene.

There is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.
Paediatric or syndromic cardiomyopathy v0.16 DES Ivone Leong reviewed gene: DES: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
Paediatric or syndromic cardiomyopathy v0.15 DES Ivone Leong Source NHS GMS was added to DES.
Paediatric or syndromic cardiomyopathy v0.13 SDHAF1 Matthew Edwards changed review comment from: None of the literature describes cardian involvement, and a cardiomyopathy is not going to be presenting feature (key symptom is leukoencephalopathy). Not appropriate for this panel.; to: None of the literature describes cardiac involvement, and a cardiomyopathy (even if present) is not going to be presenting feature (key symptom is leukoencephalopathy). Not appropriate for this panel.
Paediatric or syndromic cardiomyopathy v0.13 HGSNAT James Eden changed review comment from: Gene is associated with mucopolysaccharidosis MPS type III-C (Sanfilippo C). Cardiomyopathy has been described on one occasion as a presenting feature (PMID 21048366).; to: Gene is associated with mucopolysaccharidosis MPS type III-C (Sanfilippo C). Cardiomyopathy has been described on one occasion as a presenting feature but in a 39 year old (PMID 21048366).
Paediatric or syndromic cardiomyopathy v0.1 PCCB Ivone Leong gene: PCCB was added
gene: PCCB was added to Cardiomyopathies - including childhood onset. Sources: Expert Review Green,MetBioNet,South West GLH
Mode of inheritance for gene: PCCB was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCCB were set to 27604308
Phenotypes for gene: PCCB were set to as PCCA (metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections); DCM; Hypertrophic-hypocontractile cardiomyopathy; Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; Propionicacidemia; Propionic aciduria; Propionicacidemia 606054; Propionic acidemia; Propionic aciduria (Organic acidurias)
Paediatric or syndromic cardiomyopathy v0.1 PCCA Ivone Leong gene: PCCA was added
gene: PCCA was added to Cardiomyopathies - including childhood onset. Sources: Expert Review Green,MetBioNet,South West GLH
Mode of inheritance for gene: PCCA was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCCA were set to 27604308
Phenotypes for gene: PCCA were set to DCM; Hypertrophic-hypocontractile cardiomyopathy; Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; Propionicacidemia; Propionic aciduria; Propionicacidemia 606054; Propionic acidemia; Propionic aciduria (Organic acidurias); metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections
Paediatric or syndromic cardiomyopathy v0.1 MUT Ivone Leong gene: MUT was added
gene: MUT was added to Cardiomyopathies - including childhood onset. Sources: Expert Review Green,MetBioNet,South West GLH
Mode of inheritance for gene: MUT was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: MUT were set to 27604308
Phenotypes for gene: MUT were set to DCM; Methylmalonic aciduria, mut(0) type 251000; Hypertrophic-hypocontractile cardiomyopathy; Dehydration, hepatomegaly, lethargy, coma, acidosis, high anion gap; Methylmalonic aciduria; Methylmalonyl-CoA mutase deficiency (Organic acidurias); metabolic encephalopathy with hyperammonaemia, hypotonia, recurrent episodes of ketoacidosis, liver impairment, psychomotor retardation, recurrent infections.
Paediatric or syndromic cardiomyopathy v0.1 DES Ivone Leong gene: DES was added
gene: DES was added to Cardiomyopathies - including childhood onset. Sources: Expert Review Green,South West GLH
Mode of inheritance for gene: DES was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes for gene: DES were set to Cardiomyopathy, dilated, 1I,