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| Genomic screening in children: BabyScreen+ v0.92 | CEL |
Seb Lunke changed review comment from: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332). Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene, further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance. Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign. From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.; to: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332). Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene (pLI = 0, o/e = 0.74), further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance. Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign. From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity. |
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| Genomic screening in children: BabyScreen+ v0.92 | CEL |
Seb Lunke changed review comment from: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332). Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign. From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity.; to: Specific CEL gene variants have been associated with MODY8, and potentially hereditary chronic pancreatitis, in 5 families to date (PMID:37726640). All families have single base frame shift deletions in the VNTR (Variable Number of Tandem Repeats) region of the last exon (exon 11) of the CEL gene, specifically in the first (DEL1), fourth and fifth (DEL4,5) repeat of the VNTR region (GRCh38 chr9:133,071,168-133,071,332). Experimental evidence supports a Gain of Function, dominant negative mechanism of pathogenicity, in which certain frameshift variants cause the resulting protein to from toxic cellular aggregates (29233499). Crucially, an extended number of frameshifted repeats seem to be required to facilitate the formation of these aggregates (27650499, 38483348, 33862081). This is likely due to the increased presence of cysteine residues facilitating di-sulphide bonds, and the decreased presence of Threonine residuce that undergo O-glycosylation which is necessary for protein secretion. In addition, heterozygous NMD variants are common in gnomAD v4 for this gene, further arguing against dominant LoF as a pathogenic mechanism despite the potential for late onset and reduced penetrance. Importantly, both more distal frameshift deletions, distal single base insertions (beyond repeat 7), and frameshift variants that result in a premature termination codon in the same repeat, have no strong evidence for pathogenicity to date as they do not result in toxic protein aggregation (38483348, 33862081). Some insertions in the proximal VNTR region, in particular in the first and fourth repeat (INS1, INS4), may confer an increased risk of pancreatitis, but evidence so far remains inconclusive (PMID:38483348). More distal single base insertions (beyond repeat 7) and distal deletions have been described as likely benign. From a technical perspective, the region is challenging to map for short read NGS technologies due to the repetitive nature and high GC content. At least the five four repeats critical for MODY however are reasonably well covered in srWGS and WES data, and should be callable in routine testing. Although the fifth repeat does have increasing numbers of multimapping reads which may start to reduce sensitivity. |
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| Genomic screening in children: BabyScreen+ v0.92 | NF2 |
Lilian Rudd gene: NF2 was added gene: NF2 was added to Genomic screening in children: BabyScreen+. Sources: Expert List cancer tags were added to gene: NF2. Mode of inheritance for gene: NF2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: NF2 were set to Schwannomatosis, vestibular MIM#101000 Review for gene: NF2 was set to GREEN Added comment: EviQ guideline: From infancy Annual neurological examination3 Annual speech and pure tone audiology with auditory brainstem evoked potentials3, 4 From 10-20 years Annual cranial and spinal MRI with gadolinium enhancement (gold standard)3, 4 Once tumours are present, MRI screening should be at least annual until the individual growth rate is established.3 The ongoing interval for follow-up imaging of tumours is dependent on tumour location and growth rate3, 4 Sources: Expert List |
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| Genomic screening in children: BabyScreen+ v0.84 | KCNJ11 |
Zornitza Stark gene: KCNJ11 was added gene: KCNJ11 was added to Genomic screening in children: BabyScreen+. Sources: Literature Mode of inheritance for gene: KCNJ11 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: KCNJ11 were set to 32027066; 32376986 Phenotypes for gene: KCNJ11 were set to Monogenic diabetes MONDO:0015967, KCNJ11-related Review for gene: KCNJ11 was set to GREEN Added comment: DEFINITIVE by ClinGen. The usual mechanism for disease is heterozygous gain of function. Note multiple disease entities are associated with variants in this gene. The ClinGen Lumping and Splitting Working Group has split curations for these disease entities. The following entities have been lumped under (1) autosomal dominant monogenic diabetes, which presents as three phenotypic disease sub-entities: (1A) Permanent neonatal diabetes mellitus, (MIM:606176), (1B) Transient neonatal diabetes, 3 (MIM:125853), and less commonly, (1C) Maturity-onset diabetes of the young, type 13 (MODY13) (MIM:616329). These have been split from (2) hyperinsulinaemic hypoglycaemia, familial, 2 (MIM:601820). Sources: Literature |
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| Genomic screening in children: BabyScreen+ v0.83 | INS |
Zornitza Stark Tag treatable tag was added to gene: INS. Tag endocrine tag was added to gene: INS. |
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| Genomic screening in children: BabyScreen+ v0.82 | LDLR |
Zornitza Stark gene: LDLR was added gene: LDLR was added to Genomic screening in children: BabyScreen+. Sources: Expert Review Mode of inheritance for gene: LDLR was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LDLR were set to Hypercholesterolemia, familial, 1, MIM# 143890 Review for gene: LDLR was set to GREEN Added comment: STRONG actionability in children by ClinGen. Elevated LDL-C levels can be detected from infancy and strongly predispose patients with FH to progressive atherosclerosis throughout childhood and premature CVD in adulthood. Although complications of atherosclerosis occur most commonly in individuals aged >50, the pathophysiological processes begin in childhood and are affected by additional risk factors: hypertension, diabetes, smoking, obesity, poor diet, and physical inactivity. By 12 years of age, children with FH have significant thickening of the carotid intima-media, and by 18 years have coronary stenosis. In natural history studies, 50% of males and 25% of females with FH develop clinical CVD by age 50 years, but up to 10% can have severe premature CVD by 40 years of age. On average, individuals with HeFH experience their first coronary event at age 42, 20 years younger than the general population. Statins have changed the prognosis of FH such that the rates of cardiovascular (CV) events are equal to the general population after 10 years of treatment. Sources: Expert Review |
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| Genomic screening in children: BabyScreen+ v0.78 | GCK | Zornitza Stark Phenotypes for gene: GCK were changed from Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853); Diabetes mellitus, permanent neonatal 1, AR (MIM#606176); Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485); MODY, type II, AD (MIM#125851) to MODY, type II, AD (MIM#125851) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.76 | INS | Zornitza Stark Marked gene: INS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.76 | INS | Zornitza Stark Gene: ins has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.76 | INS | Zornitza Stark Phenotypes for gene: INS were changed from monogenic diabetes MONDO:0015967; Diabetes mellitus, insulin-dependent, 2, MIM# 125852; Diabetes mellitus, permanent neonatal 4, MIM# 618858; Maturity-onset diabetes of the young, type 10, MIM# 613370 to monogenic diabetes MONDO:0015967 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.75 | NEUROD1 | Zornitza Stark Phenotypes for gene: NEUROD1 were changed from Maturity Onset Diabetes of the Young; {Diabetes mellitus, noninsulin-dependent}, 125853 to Maturity-onset diabetes of the young 6, MIM#606394 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.71 | NEUROD1 |
Zornitza Stark gene: NEUROD1 was added gene: NEUROD1 was added to Genomic screening in children: BabyScreen+. Sources: Expert Review Green,Royal Melbourne Hospital,Victorian Clinical Genetics Services Mode of inheritance for gene: NEUROD1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: NEUROD1 were set to 25477324; 25684977; 22784109; 29521454 Phenotypes for gene: NEUROD1 were set to Maturity Onset Diabetes of the Young; {Diabetes mellitus, noninsulin-dependent}, 125853 |
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| Genomic screening in children: BabyScreen+ v0.70 | Zornitza Stark Copied gene INS from panel Maturity-onset Diabetes of the Young | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic screening in children: BabyScreen+ v0.70 | INS |
Zornitza Stark gene: INS was added gene: INS was added to Genomic screening in children: BabyScreen+. Sources: Expert Review Green,Royal Melbourne Hospital,Victorian Clinical Genetics Services Mode of inheritance for gene: INS was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: INS were set to 18162506; 9884331 Phenotypes for gene: INS were set to monogenic diabetes MONDO:0015967; Diabetes mellitus, insulin-dependent, 2, MIM# 125852; Diabetes mellitus, permanent neonatal 4, MIM# 618858; Maturity-onset diabetes of the young, type 10, MIM# 613370 |
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| Genomic screening in children: BabyScreen+ v0.68 | GCK |
Zornitza Stark gene: GCK was added gene: GCK was added to Genomic screening in children: BabyScreen+. Sources: Expert Review Green,Royal Melbourne Hospital Mode of inheritance for gene: GCK was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal Publications for gene: GCK were set to 19790256 Phenotypes for gene: GCK were set to Diabetes mellitus, noninsulin-dependent, late onset, AD (MIM#125853); Diabetes mellitus, permanent neonatal 1, AR (MIM#606176); Hyperinsulinemic hypoglycemia, familial, 3, AD (MIM#602485); MODY, type II, AD (MIM#125851) |
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| Genomic screening in children: BabyScreen+ v0.54 | TECRL |
Lilian Rudd gene: TECRL was added gene: TECRL was added to Genomic screening in children: BabyScreen+. Sources: Expert list Mode of inheritance for gene: TECRL was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TECRL were set to Ventricular tachycardia, catecholaminergic polymorphic, 3, MIM# 614021 Review for gene: TECRL was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. Not on ACMG additional findings list. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Sources: Expert list |
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| Genomic screening in children: BabyScreen+ v0.50 | TRDN |
Lilian Rudd gene: TRDN was added gene: TRDN was added to Genomic screening in children: BabyScreen+. Sources: Expert list Mode of inheritance for gene: TRDN was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: TRDN were set to Cardiac arrhythmia syndrome, with or without skeletal muscle weakness, MIM# 615441 Review for gene: TRDN was set to GREEN Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years. Reviewed with paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. Sources: Expert list |
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| Genomic screening in children: BabyScreen+ v0.47 | ZBTB24 |
Lilian Rudd gene: ZBTB24 was added gene: ZBTB24 was added to Genomic screening in children: BabyScreen+. Sources: Expert list Mode of inheritance for gene: ZBTB24 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ZBTB24 were set to PMID: 28128455, 21906047, 21596365, 23486536 Phenotypes for gene: ZBTB24 were set to Immunodeficiency-centromeric instability-facial anomalies syndrome 2 MIM#614069 Review for gene: ZBTB24 was set to AMBER Added comment: Infant onset Agammaglobulinemia, facial anomalies, and mental retardation. Facial anomalies included broad, flat nasal bridge, hypertelorism, and epicanthal folds. Treat immunoglobulin and bone marrow transplant however, this only treats the immune deficiency. ?For childhood screening or just for ID opt in. Sources: Expert list |
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| Genomic screening in children: BabyScreen+ v0.33 | JUP |
Zornitza Stark edited their review of gene: JUP: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 12 MIM# 611528, Naxos disease MIM# 601214; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal |
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| Genomic screening in children: BabyScreen+ v0.31 | HNF4A |
Zornitza Stark edited their review of gene: HNF4A: Added comment: At the milder end of the spectrum, variants in this gene are associated with MODY. Treatment of hyperinsulinism: diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus.; Changed phenotypes: MODY, type I, OMIM # 125850 |
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| Genomic screening in children: BabyScreen+ v0.24 | DSP |
Zornitza Stark edited their review of gene: DSP: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 8, MIM# 607450 |
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| Genomic screening in children: BabyScreen+ v0.22 | DSG2 |
Zornitza Stark edited their review of gene: DSG2: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 10, MIM# 610193 |
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| Genomic screening in children: BabyScreen+ v0.19 | DSC2 |
Zornitza Stark edited their review of gene: DSC2: Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen together with other ARVC genes. ARVC is a progressive heart disease characterized by degeneration of cardiac myocytes and their subsequent replacement by fat and fibrous tissue primarily in the right ventricle, though the left ventricle may also be affected. It is associated with an increased risk of ventricular arrhythmia (VA) and sudden cardiac death (SCD) in young individuals and athletes. The VA is usually in proportion to the degree of ventricular remodeling and dysfunction, and electrical instability. The mechanism of SCD is cardiac arrest due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Age of onset is highly variable with a mean age of diagnosis of 31 years and a range of 4 to 64 years. Antiarrhythmic drugs and beta-blockers are not recommended in healthy gene carriers. In patients with ARVC and ventricular arrhythmia (VA), a beta-blocker or other antiarrhythmic is recommended. Recommendations for ICD placement in patients with ARVC differ across guidelines, both in terms of the indications for placement and whether recommendations are based on evidence or expert opinion. Recommendations based on non-randomized studies support ICD placement in patients with ARVC and an additional marker of increased risk of SCD (resuscitated SCA, sustained VT hemodynamically tolerated, and significant ventricular dysfunction with RVEF or LVEF ≤35%) and in patients with ARVC and syncope presumed to be due to VA if meaningful survival greater than 1 year is expected. The presence of a combination of other risk factors (e.g., male sex, frequent PVCs, syncope) may also be used to indicate implantation. Serial screening for the emergence of cardiomyopathy is recommended for clinically unaffected individuals who carry a variant associated with ARVC, including: • Medical history, with special attention to heart failure symptoms, arrhythmias, presyncope or syncope, and thromboembolism • Physical examination with special attention to cardiac and neuromuscular systems and examination of the integumentary system if ARVC is suspected • Electrocardiography • Cardiovascular imaging. Penetrance: In a study of 264 probands with genetic variants associated with ARVC who presented alive, 73% had sustained VA, 13% had symptomatic HF, and 5% had cardiac death (2% SCD, 2% HF, and 1% HF with VA) during median 8-year follow-up. Among 385 family members of the probands who also carried an ARVC variant, 32% met clinical criteria for ARVC, 11% experienced sustained VA, and 2% died during follow-up (1% from SCD, 0.5% from HF, and 0.5% non-cardiac issues). In a second study of 220 probands with genetic variants associated with ARVC who presented alive, 54% presented with sustained VT. In 321 family members of the probands who also carried an ARVC variant, 14% were symptomatic at presentation but 8% experienced VA during a mean 4-year follow-up. For all 541 cases, 60% met clinical criteria for ARVC, 30% had sustained VA, 14% developed ventricular dysfunction, 5% experienced HF, 4% had a resuscitated SCD/VF, and 2% died over a mean follow-up of 6 years.; Changed phenotypes: Arrhythmogenic right ventricular dysplasia 11, MIM# 610476, Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair, MIM# 610476; Changed mode of inheritance: BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal |
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| Genomic screening in children: BabyScreen+ v0.17 | COL3A1 |
Zornitza Stark edited their review of gene: COL3A1: Added comment: Well established gene-disease association. Assessed as 'moderate actionability' in paediatric patients by ClinGen. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. The majority (60%) of individuals diagnosed before age 18 are identified because of a positive family history, though 15% of children have experienced a major complication before the time of testing, and of those tested in the absence of family history, 54% had experienced a major complication. Death in the first two decades of life most commonly results from arterial rupture; death before age 20 is more commonly reported in males (3:1). Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with a COL3A1 pathogenic variant, and may present as sudden death, stroke and neurologic sequelae, acute abdomen/retroperitoneal bleeding, uterine rupture at delivery, and/or shock, with an average age of 31 for first major arterial or gastrointestinal complication. Bowel rupture is very rarely (3%) lethal. Hemoptysis can be severe and recurrent, even life threatening. Carotid cavernous sinus fistulas typically present with sudden-onset ocular symptoms and almost always require rapid intervention to save vision. It affects about 10% of individuals with vEDS with a preponderance among females. Vascular fragility is dominant in the third and fourth decade. Imaging of the entire arterial tree is recommended. Lack of consensus re aortic repair: Guidelines differ on recommendation for prophylactic aortic repair in the case of asymptomatic patients with aortic aneurysm. Some guidelines recommend patients undergo elective operation at diameters of 4.0-6.0 cm depending on location of aortic aneurysm and pregnancy anticipation status. Other guidelines take a more conservative approach, stating that due to the high risk of complications as a result of hemorrhagic tendency, tissue fragility, and poor wound healing in vEDS as well as the lack of specific data in vEDS patients, it is not possible to set threshold for surgical intervention in patients with EDS Type IV and thoracic aortic aneurysm. These guidelines state that decisions to surgically intervene should instead be based on a case-by-case basis and guided by multidisciplinary discussion. On ACMG SF list.; Changed phenotypes: Ehlers-Danlos syndrome, vascular type, MIM# 130050 |
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| Genomic screening in children: BabyScreen+ v0.13 | CALM2 |
Zornitza Stark edited their review of gene: CALM2: Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.; Changed phenotypes: Catecholaminergic polymorphic ventricular tachycardia MONDO:0017990 |
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| Genomic screening in children: BabyScreen+ v0.11 | CALM1 |
Zornitza Stark edited their review of gene: CALM1: Added comment: Rated as 'strong actionability' for paediatric patients by ClinGen. The mean age of onset of symptoms (usually a syncopal episode) of CPVT is between age seven and twelve years; onset as late as the fourth decade of life has been reported. Nearly 60% of patients have at least one syncopal episode before age 40. If untreated, CPVT is highly lethal, as approximately 30% of genetically affected individuals experience at least one cardiac arrest and up to 80% one or more syncopal spells. In untreated patients, the 8-year fatal or near-fatal event rates of 25% have been reported. Sudden death may be the first manifestation of the disease. Instances of sudden infant death syndrome (SIDS) have been associated with pathogenic variants in RYR2. Individuals with pathogenic variants in CALM1, CALM2 or CALM3 can have a severe phenotype, with earlier onset, QT prolongation, and a high predilection for cardiac arrest and sudden death. Beta-blockers lacking intrinsic sympathomimetic activity are recommended as a first-line therapy in all patients with a clinical diagnosis of CPVT, including those with documented spontaneous, stress-induced VAs. Guidelines differ in their recommendations about utilizing beta-blocker therapy in phenotype negative individuals. Treatment with beta blockers is associated with a reduction in adverse cardiac events. However, variability in outcome with beta-blocker therapy is due to multiple factors, including dosing and compliance. In a study of 101 patients with CPVT (22 diagnosed clinically and 79 diagnosed molecularly), 81 were administered beta-blockers (57 symptomatic and 24 asymptomatic individuals). Estimated 4- and 8-year cardiac event rates were 8% and 27%, respectively in patients taking beta-blockers, and 33% and 58% in those not taking beta blockers (log-rank p=0.01). Corresponding statistics for fatal events were 1% and 11% with beta-blockers vs. 18% and 25% without (log-rank p=0.05). Event rates in asymptomatic patients with a positive genotype were similar to other patients. In multivariate models, absence of beta-blockers was an independent predictor of cardiac events (hazard ratio [HR], 5.48; 95% CI, 1.8 to 16.7, p=0.003) and of fatal events (HR, 5.54; 95% CI, 1.2 to 26.1, p=0.03). Of the 37 asymptomatic patients with a positive genotype, 9 (24%) had cardiac events. In patients with CPVT and recurrent sustained VT or syncope, while receiving adequate or maximally tolerated beta blocker, treatment intensification with either combination medication therapy (e.g., beta blocker with flecainide), left cardiac sympathetic denervation, and/or an ICD is recommended. Clinical penetrance ranges from 25 to 100%, with an average of 70 to 80%. Syncope appears to be the first symptom in more than half of the patients. When untreated, mortality from CPVT is high, reaching 30 to 50% by the age of 30 years.; Changed phenotypes: Ventricular tachycardia, catecholaminergic polymorphic, 4, MIM# 614916 |
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