| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Genomic newborn screening: BabyScreen+ v1.110 | ELANE |
Zornitza Stark commented on gene: ELANE: ClinGen: there is little evidence for haploinsufficiency. gnomAD pLI score is zero and there are NMD predicted variants in the population. Entire gene deletion is not described in the context of neutropenia, including deletion of 19p terminal (encompassing ELANE) (PMID: 33968054). Maturation arrest, the failure of the marrow myeloid progenitors to form mature neutrophils, is a consistent feature of ELANE associated congenital neutropenia. Knock-out of the mutant allele in hematopoietic stem cells derived from SCN patients restores neutrophils maturation (PMID: 3124897). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v1.23 | TRAC |
Zornitza Stark gene: TRAC was added gene: TRAC was added to BabyScreen+ newborn screening. Sources: Expert Review founder, technically challenging tags were added to gene: TRAC. Mode of inheritance for gene: TRAC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRAC were set to 21206088 Phenotypes for gene: TRAC were set to Immunodeficiency 7, TCR-alpha/beta deficient, MIM#615387 Review for gene: TRAC was set to RED Added comment: Single variant reported to date in 6 patients; 2 unrelated children from consanguineous families of Pakistani descent (PMID: 21206088); 1 non-consanguineous family from North-west India (PMID: 33909184) and 1 consanguineous parents of East Indian (https://lymphosign.com/doi/10.14785/lymphosign-2022-0001) Also note annotation issues in certain variant curation and annotation tools. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.2131 | PRKG1 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Discussed with a paediatric cardiologist: variable penetrance and age of onset, does not fulfil criteria for gNBS. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.2130 | MYH11 |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair.; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 12 individuals with MYH11 pathogenic variants indicated that 34% had an aortic dissection and one individual (8%) underwent prophylactic aortic aneurysm repair. Reviewed with a paediatric cardiologist: variable penetrance and age of onset, does not meet criteria for gNBS. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.2129 | LOX |
Zornitza Stark changed review comment from: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen; to: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Discussed with paediatric cardiologist: variable penetrance and age of onset, does not fit with criteria for gNBS. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.2035 | NAXD |
Zornitza Stark gene: NAXD was added gene: NAXD was added to Baby Screen+ newborn screening. Sources: Expert list treatable, metabolic tags were added to gene: NAXD. Mode of inheritance for gene: NAXD was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: NAXD were set to 30576410; 31755961; 32462209; 35231119 Phenotypes for gene: NAXD were set to Encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 2 MIM#618321 Review for gene: NAXD was set to AMBER Added comment: Seven unrelated cases, episodes of fever/infection prior to deterioration reported. Variable phenotype: one patient reported with neurodevelopmental disorder, autism spectrum disorder and a muscular-dystrophy-like myopathy; another with progressive encephalopathy with brain oedema. Patient cells and muscle biopsies also showed impaired mitochondrial function, higher sensitivity to metabolic stress, and decreased mitochondrial reactive oxygen species production. In vitro functional assays also conducted. Treatment: niacin However, only two cases reported. Treatment not established. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.2009 | IL36RN |
Zornitza Stark gene: IL36RN was added gene: IL36RN was added to Baby Screen+ newborn screening. Sources: Expert list treatable, immunological tags were added to gene: IL36RN. Mode of inheritance for gene: IL36RN was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: IL36RN were set to 31286990 Phenotypes for gene: IL36RN were set to Psoriasis 14, pustular, MIM# 614204 Review for gene: IL36RN was set to GREEN Added comment: Generalized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein. Variable age of onset but predominantly in infancy/early childhood. Treatment: ustekinumab, secukinumab, etanercept. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1982 | TPK1 |
Lilian Downie gene: TPK1 was added gene: TPK1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TPK1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TPK1 were set to PMID: 33086386, 32679198, 22152682, PMID: 33231275 Phenotypes for gene: TPK1 were set to Thiamine metabolism dysfunction syndrome 5 (episodic encephalopathy type) MIM#614458 Review for gene: TPK1 was set to GREEN Added comment: Strong gene disease association Variable age of onset but always under 5years Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). Biotin and thiamine therapy - newer evidence (2021) suggests early thiamine therapy may prevent any neurologic deficits. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1982 | TRPM6 |
Lilian Downie gene: TRPM6 was added gene: TRPM6 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: TRPM6 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TRPM6 were set to PMID: 35903165, PMID: 18818955 Phenotypes for gene: TRPM6 were set to Hypomagnesemia 1, intestinal MIM#602014 Review for gene: TRPM6 was set to GREEN Added comment: Hypomagnaesemia and hypocalcaemia Hypocalcemia is a secondary consequence of parathyroid failure and parathyroid hormone resistance as a result of severe magnesium deficiency. The disease typically manifests during the first months of life with generalized convulsions or signs of increased neuromuscular excitability, such as muscle spasms or tetany. Untreated, the disease may be fatal or lead to severe neurologic damage. Treatment includes immediate administration of magnesium, usually intravenously, followed by life-long high-dose oral magnesium (review by Knoers, 2009). Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1967 | GPIHBP1 |
Zornitza Stark gene: GPIHBP1 was added gene: GPIHBP1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: GPIHBP1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: GPIHBP1 were set to 31390500 Phenotypes for gene: GPIHBP1 were set to Hyperlipoproteinemia, type 1D MIM#615947; familial chylomicronemia syndrome Review for gene: GPIHBP1 was set to GREEN Added comment: Well-established gene-disease association. Usually presents in childhood with episodes of abdominal pain, recurrent acute pancreatitis, eruptive cutaneous xanthomata, and hepatosplenomegaly. Approximately 25% of affected children develop symptoms before age one year and the majority develop symptoms before age ten years; however, some individuals present for the first time during pregnancy. Treatment: volanesorsen, dietary fat restriction Non-genetic confirmatory testing: triglyceride level Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1958 | VKORC1 |
Lilian Downie gene: VKORC1 was added gene: VKORC1 was added to Baby Screen+ newborn screening. Sources: Expert list Mode of inheritance for gene: VKORC1 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: VKORC1 were set to PMID:14765194, PMID: 26287237 Phenotypes for gene: VKORC1 were set to Vitamin K-dependent clotting factors, combined deficiency of, 2 MIM#607473 Review for gene: VKORC1 was set to AMBER Added comment: Risk of intracranial haemmorhage in first weeks of life Treatable with vitamin K See below summary - feels like should be green for that homozygous mutation but not sure how to manage the gene overall? not report other variants? Monoallelic - warfarin resistance There is only one mutation known to result in the VKCFD2 phenotype. VKORC1:p.Arg98Trp causes diminished vitamin K epoxide reductase (VKOR) activity compared to that of the wild-type enzyme [15]. VKCFD2 patients exhibit severely diminished activities for the VKD coagulation factors and suffer spontaneous or surgery/injury induced bleeding episodes [16,17]. In addition to this haemorrhagic phenotype, abnormalities in epiphyseal growth have been reported in one case [18]. This phenotype is very rare. Worldwide, there are only four unrelated families known to be affected with VKCFD2 [16,17,18]. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1918 | CD3G |
Zornitza Stark gene: CD3G was added gene: CD3G was added to gNBS. Sources: Expert list Mode of inheritance for gene: CD3G was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD3G were set to 31921117 Phenotypes for gene: CD3G were set to Immunodeficiency 17; CD3 gamma deficient MIM# 615607 Added comment: 10 affected individuals from 5 unrelated families; homozygous and compound heterozygous variants (splicing, missense and small deletion variants) identified resulting in premature stop codons and truncated protein; multiple mouse models. All individuals displayed immune deficiency and autoimmunity of variable severity. Some individuals presented at birth with failure to thrive due to lethal SCID features. The most common immunologic profile includes partial T lymphocytopenia and low CD3, with normal B cells, NK cells, and immunoglobulins. Congenital onset. Treatment: replacement immunoglobulin Non-genetic confirmatory testing: immunoglobulin levels Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1872 | HMGCS2 |
Lilian Downie gene: HMGCS2 was added gene: HMGCS2 was added to gNBS. Sources: Expert list Mode of inheritance for gene: HMGCS2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HMGCS2 were set to PMID: 32259399, 32470406 Phenotypes for gene: HMGCS2 were set to HMG-CoA synthase-2 deficiency MIM#605911 Penetrance for gene: HMGCS2 were set to Incomplete Review for gene: HMGCS2 was set to AMBER Added comment: Metabolic disorder; patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. Recover completely between illnesses, do develop fatty liver. ?incomplete penetrance or variable age of onset On GUARDIAN and Rx Genes Rx IV glucose during acute episodes, avoid prolonged fasting Metabolic parameters are normal in between episodes, so no ability to do a confirmatory biochemical test. Pros: readily treatable if child has an episode Cons: unncessary worry as child may never have episode Super rare ?30 cases Discuss with JC? Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1865 | TANGO2 |
Ari Horton changed review comment from: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review; to: Folate may assist with TANGO2 DOI: https://doi.org/10.21203/rs.3.rs-1778084/v1 PMID: 35568137 While chronic symptoms are predominantly neurodevelopmental, metabolic stressors such as fasting, dehydration, illness, and excessive heat can trigger episodic metabolic crises characterized by encephalopathy, ataxia, muscle weakness, rhabdomyolysis, and hypoglycemia. During these events, patients can develop acute life-threatening cardiac arrhythmias. Arrhythmias typically initiate with isolated premature ventricular contractions (PVC) followed by recalcitrant ventricular tachycardia. Because these lethal arrhythmias usually do not respond to standard antiarrhythmic therapies, cardiac arrhythmias are the leading cause of death in TDD Fasting and feeding recommendations to reduce crises and improve cardiac status and neurodev outcomes, reduce risk of cardiac arrhythmias and SCDY Natural history study (ClinicalTrials.gov Identifier: NCT05374616) strongly suggests that subjects on a multivitamin or a Bcomplex vitamin supplement have a greatly reduced risk for metabolic crises and cardiac arrhythmias Twenty-seven children were admitted for 43 cardiac crises (median age 6.4 years; interquartile range [IQR] 2.4–9.8 years) at 14 centers. During crisis, QTc prolongation occurred in all (median 547 ms; IQR 504–600 ms) and a type I Brugada pattern in 8 (26%). Arrhythmias included VT 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. There were 10 deaths (37%), 6 related to arrhythmias. In 5 patients, recalcitrant VT occurred despite use of antiarrhythmic drugs. In 6 patients, arrhythmias were controlled after extracorporeal membrane oxygenation (ECMO) support; 5 of these patients survived. Among 10 patients who survived VT without ECMO, successful treatment included intravenous magnesium, isoproterenol, and atrial pacing in multiple cases and verapamil in 1 patient. Initiation of feeds seemed to decrease VT events. Specific diet and fasting plans are recommended for all patients from the neonatal period Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1860 | HBA1 |
Zornitza Stark changed review comment from: Well established gene-disease association. Congenital onset. Treatable: transfusions, bone marrow transplant. However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? For review.; to: Well established gene-disease association. Congenital onset. Treatable: transfusions, bone marrow transplant. However, there is widespread screening in pregnancy. Also note mutational spectrum includes SVs/CNVs: can we reliably diagnose? Exclude for now due to technical concerns. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1781 | PRKG1 |
Zornitza Stark gene: PRKG1 was added gene: PRKG1 was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: PRKG1. Mode of inheritance for gene: PRKG1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: PRKG1 were set to Aortic aneurysm, familial thoracic 8, MIM#615436 Penetrance for gene: PRKG1 were set to Incomplete Review for gene: PRKG1 was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 31 individuals with PRKG1 pathogenic variants indicated that 63% presented with an aortic dissection and 37% had aortic root enlargement. The cumulative risk of an aortic dissection or repair of an aortic aneurysm by age 55 has been estimated as 86% (95% CI: 70-95%). Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1778 | LOX |
Zornitza Stark gene: LOX was added gene: LOX was added to gNBS. Sources: ClinGen for review, cardiac, treatable tags were added to gene: LOX. Mode of inheritance for gene: LOX was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: LOX were set to Aortic aneurysm, familial thoracic 10, MIM#617168 Penetrance for gene: LOX were set to Incomplete Review for gene: LOX was set to AMBER Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. FTAAD is a rare genetic vascular disease characterized by the familial occurrence of thoracic aortic aneurysm, dissection, or dilatation affecting one or more aortic segments (aortic root, ascending aorta, arch, or descending aorta). Variable age of clinical presentation. Prophylactic surgical repair of the aorta is recommended at 4.5-5.0 cm for patients with pathogenic variants in MYH11, SMAD3, and ACTA2 and at 4.0-4.5 cm for patients with pathogenic variants in TGFBR1 or TGFBR2. Beta adrenergic-blocking agents are recommended to reduce aortic dilation. Losartan was added as an alternative to beta adrenergic-blocking agents in FTAAD after studies showed its efficacy in children and young adults with MFS who were randomly assigned to losartan or atenolol. Penetrance: A study of 15 individuals with LOX pathogenic variants indicated that 73% had aortic aneurysms and 1 individual (7%) had an aortic dissection. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1772 | RUNX1 |
Zornitza Stark gene: RUNX1 was added gene: RUNX1 was added to gNBS. Sources: ClinGen for review, treatable, haematological tags were added to gene: RUNX1. Mode of inheritance for gene: RUNX1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: RUNX1 were set to Platelet disorder, familial, with associated myeloid malignancy, MIM# 601399 Review for gene: RUNX1 was set to AMBER Added comment: Assessed as 'moderate actionability' in paediatric patients by ClinGen. HTHCPS is characterized by mild to moderate thrombocytopenia with normal platelet size, abnormal platelet functioning (defective release of delta granules and/or aggregation defects), and an increased risk of developing a haematologic malignancy. Age of onset of bleeding can be highly variable, with some individuals presenting in early infancy and others not recognizing their symptoms until much later in life. Severe thrombocytopenia or profound platelet dysfunction can result in recognition during the perinatal or infancy period. Hematologic malignancies can occur in childhood or adulthood; the range of age of onset is wide with a median age of 33 years. Use of clotting promotors (e.g., desmopressin, epsilon aminocaproic acid, tranexamic acid) can be used for surgeries, injuries, or dental treatments. Platelet transfusions may be used for severe bleeding or procedures with a high bleeding risk. Though there is no specific treatment for HTHCPS, there are recommendations regarding the indications and timing of hematopoietic stem cell transplantation (HSCT) that vary. HSCT in pre-malignancy patients, particularly in the absence of any clonal progression, is debatable due to transplantation-associated risks and incomplete penetrance. Some suggested indications for HSCT include severe or symptomatic cytopenias, severe marrow dysplasia (particularly in the context of falling blood counts), complex or high-risk (e.g., monosomy 7) cytogenetic abnormalities (particularly if the clones are large or increasing in size) and increasing blasts >5%. Consider use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1740 | TGFB2 |
Zornitza Stark gene: TGFB2 was added gene: TGFB2 was added to gNBS. Sources: ClinGen Mode of inheritance for gene: TGFB2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: TGFB2 were set to Loeys-Dietz syndrome 4, MIM# 614816 Review for gene: TGFB2 was set to GREEN Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen. Individuals with LDS are predisposed to widespread and aggressive arterial aneurysms which are the major source of morbidity and mortality. Aortic growth can be faster than 10mm per year. Aortic dissection has been observed in early childhood, and the mean age of death is 26 years. Other life-threatening manifestations include spontaneous rupture of the spleen, bowel, and uterine rupture during pregnancy. Prophylactic surgical repair is typically recommended at an aortic diameter of ≥ 4.2 cm. Beta-blockers or other medications can be used to reduce hemodynamic stress. Consider Medicalert bracelet. Use of subacute bacterial endocarditis prophylaxis should be considered for individuals with connective tissue disorders and documented evidence of mitral and/or aortic regurgitation who are undergoing dental work or other procedures expected to contaminate the bloodstream with bacteria. Because of a high risk of cervical spine instability, a flexion and extension x-ray of the cervical spine should be performed prior to intubation or any other procedure involving manipulation of the neck. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1728 | RPE65 |
Zornitza Stark gene: RPE65 was added gene: RPE65 was added to gNBS. Sources: ClinGen for review, treatable, ophthalmological tags were added to gene: RPE65. Mode of inheritance for gene: RPE65 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: RPE65 were set to Leber congenital amaurosis 2 MIM#204100; Retinitis pigmentosa 20 MIM#613794 Review for gene: RPE65 was set to GREEN Added comment: Assessed as 'strong actionability' in paediatric patients by ClinGen. Biallelic RPE65 mutation-associated retinal dystrophy is a form of IRD caused by biallelic pathogenic variants in RPE65; it presents as a spectrum of disease with variable age of onset and progression of vision loss. Common clinical findings across the spectrum include night blindness, progressive loss of visual fields and loss of central vision. In LCA, night blindness often occurs from birth. Characteristically, these patients have residual cone-mediated vision in the first to third decades with progressive visual field loss until complete blindness is observed, most often in mid- to late-adulthood. A range of age of onset has been described for night blindness in RP, but it typically onsets in later childhood. In December 2017, the FDA approved LUXTURNA (voretigene neparvovec-rzyl) gene therapy for the treatment of patients with confirmed biallelic RPE65 mutation-associated retinal dystrophy. The FDA’s conclusion of efficacy is based on improvement in a functional vision score over 1 year in a single open-label controlled Phase 3 study of 31 affected patients. The average age of the 31 randomized patients was 15 years (range 4 to 44 years), including 64% pediatric subjects (n=20, age from 4 to 17 years) and 36% adults (n=11). Functional vision was scored by a patient’s ability to navigate a course in various luminance levels. Using both treated eyes of the 21 subjects in the LUXTURNA treatment group, 11 (52%) had a clinically meaningful score improvement, while only one of the ten (10%) subjects in the control group had a clinically meaningful score improvement. Using the first treated eye only, 15/21 (71%) had a clinically meaningful score improvement, while no comparable score improvement was observed in controls. Other secondary clinical outcomes were also examined. Analysis of white light full-field light sensitivity threshold testing showed statistically significant improvement at 1 year in the LUXTURNA treatment group compared to the control group. The change in visual acuity was not significantly different between the LUXTURNA and control groups. LUXTURNA is administered subretinally by injection. Per the FDA package insert, the most common adverse reactions (incidence ≥ 5%) in the clinical trials for LUXTURNA included conjunctival hyperemia, cataract, increased intraocular pressure, retinal tear, dellen (thinning of the corneal stroma), and macular hole. Several other ocular adverse effects were also reported, including risk of endophthalmitis. Safety data was included on the basis of 41 patients (81 eyes). For review: availability of therapy? Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1724 | ITGB3 |
Zornitza Stark gene: ITGB3 was added gene: ITGB3 was added to gNBS. Sources: ClinGen treatable, haematological tags were added to gene: ITGB3. Mode of inheritance for gene: ITGB3 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITGB3 were set to Glanzmann thrombasthenia 2, MIM# 619267 Review for gene: ITGB3 was set to GREEN Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen. GT can present soon after birth with episodic mucocutaneous bleeding, purpura, petechiae, unprovoked bruising, and excessive bleeding from the umbilical stump or post-circumcision. Major bleeding complications during the neonatal period, such as ICH following delivery are rare. The clinical severity of GT tends to diminish with age, although the bleeding manifestations persist and are life-long. Recombinant activated factor VII (rFVIIa) may be considered for patients with: moderate to severe acute bleeding; for treatment of refractory minor bleeds; for prophylaxis in patients with frequent severe bleeds; treatment during minor and major surgery; and in patients who are refractory to platelet transfusion. Some guidelines suggest utilizing rFVIIa as a first line therapy and saving platelet transfusion for more severe or non-responsive bleeds. High doses have been successful, particularly if used early and upfront. rFVIIa in a dose of =80 µg/kg at intervals of 2.5 h or less were observed to be safe and effective in nonsurgical bleeds, minor and major procedures in patients with or without antibodies, and/or refractoriness. The International Glanzmann Thrombasthenia Registry (GTR), published in 2015, studied 184 patients with 829 bleeding episodes and 96 patients with 206 surgical interventions. rFVIIa alone was used in 124/829 bleeds and the proportion of successful treatment to stop bleeding was 91%. In patients without antibodies/refractoriness, rFVIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for 24 minor and 4 major procedures. The lowest effectiveness of rFVIIa treatment alone was 88.9% (16/18 effective minor procedures) in refractory patients with platelet antibodies. Desmopressin (DDAVP) may be considered as an additional treatment for mild bleeding episodes. DDAVP has been shown to be effective in many bleeding disorders, including inherited platelet function disorders. However, DDAVP efficacy among GT patients has not been established and guideline recommendations are conflicting. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1722 | ITGA2B |
Zornitza Stark gene: ITGA2B was added gene: ITGA2B was added to gNBS. Sources: ClinGen treatable, haematological tags were added to gene: ITGA2B. Mode of inheritance for gene: ITGA2B was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ITGA2B were set to Glanzmann thrombasthaenia 1, MIM# 273800 Review for gene: ITGA2B was set to GREEN Added comment: Rated as 'strong actionability' in paediatric patients by ClinGen. GT can present soon after birth with episodic mucocutaneous bleeding, purpura, petechiae, unprovoked bruising, and excessive bleeding from the umbilical stump or post-circumcision. Major bleeding complications during the neonatal period, such as ICH following delivery are rare. The clinical severity of GT tends to diminish with age, although the bleeding manifestations persist and are life-long. Recombinant activated factor VII (rFVIIa) may be considered for patients with: moderate to severe acute bleeding; for treatment of refractory minor bleeds; for prophylaxis in patients with frequent severe bleeds; treatment during minor and major surgery; and in patients who are refractory to platelet transfusion. Some guidelines suggest utilizing rFVIIa as a first line therapy and saving platelet transfusion for more severe or non-responsive bleeds. High doses have been successful, particularly if used early and upfront. rFVIIa in a dose of =80 µg/kg at intervals of 2.5 h or less were observed to be safe and effective in nonsurgical bleeds, minor and major procedures in patients with or without antibodies, and/or refractoriness. The International Glanzmann Thrombasthenia Registry (GTR), published in 2015, studied 184 patients with 829 bleeding episodes and 96 patients with 206 surgical interventions. rFVIIa alone was used in 124/829 bleeds and the proportion of successful treatment to stop bleeding was 91%. In patients without antibodies/refractoriness, rFVIIa, either alone or with antifibrinolytics, and platelets±antifibrinolytics were rated 100% effective for 24 minor and 4 major procedures. The lowest effectiveness of rFVIIa treatment alone was 88.9% (16/18 effective minor procedures) in refractory patients with platelet antibodies. Desmopressin (DDAVP) may be considered as an additional treatment for mild bleeding episodes. DDAVP has been shown to be effective in many bleeding disorders, including inherited platelet function disorders. However, DDAVP efficacy among GT patients has not been established and guideline recommendations are conflicting. Sources: ClinGen |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1721 | F7 |
Zornitza Stark changed review comment from: Well established gene-disease association. Variable severity. Treatment: Recombinant coagulation Factor VIIa Non-genetic confirmatory testing: factor VII level; to: Well established gene-disease association. Variable severity. Treatment: Recombinant coagulation Factor VIIa Non-genetic confirmatory testing: factor VII level Rated as 'strong actionability' in paediatric patients by ClinGen. Clinical expression of factor VII deficiency is highly variable, and no consistent relationship has been found between the severity of the hemorrhagic syndrome and the residual levels of FVII activity. Individuals can be completely asymptomatic despite a very low FVII level. A bleeding history appears more predictive of further bleeding than the factor VII level. Factor VII levels increase during pregnancy, but levels usually remain insufficient for hemostasis in severely affected cases. Individuals with no history of bleeding do not appear to be at increased risk of PPH. Heterozygotes often have approximately half-normal levels of coagulation factors and are often asymptomatic. However, up to 2% of patients with severe bleeding phenotype are heterozygotes. Consider prophylaxis using rFVIIa in certain circumstances. Long term prophylaxis should be considered for cases with a personal or family history of severe bleeding or with FVII activity <0.01 IU/ml using rFVIIa, adjusting to maintain clinical response. Short term prophylaxis should be considered for cases for neonates without a personal or family history of severe bleeding but who have FVII activity 0.01-0.05 IU/ml up to 6-12 months of age. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1710 | COL9A1 |
David Amor changed review comment from: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment. Severity: moderate-severe Age of onset: congenital Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia Treatment: as per other Stickler syndrome; to: Gene-disease association: strong but rare, prbably <1% of Sticller syndrome; Van Camp et al. (2006) described a consanguineous Moroccan family in which 4 of 10 sibs had features characteristic of Stickler syndrome, including moderate to severe sensorineural hearing loss, moderate to high myopia with vitreoretinopathy, and epiphyseal dysplasia. Nikopoulos et al. (2011) reported 2 sisters in a Turkish family and 1 boy in a Moroccan family with features of autosomal recessive Stickler syndrome. All 3 individuals had myopia, vitreous changes, sensorineural hearing loss, and epiphyseal dysplasia. They also had exudative rhegmatogenous retinal detachment. Severity: moderate-severe Age of onset: congenital Non-molecular confirmatory testing: Affected individuals have moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, cataracts, and epiphyseal dysplasia Treatment: as per other Stickler syndrome |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1600 | POLG | Zornitza Stark Phenotypes for gene: POLG were changed from POLG-Related Ataxia Neuropathy Spectrum Disorders to Mitochondrial DNA depletion syndrome 4A (Alpers type) MIM#203700; Mitochondrial DNA depletion syndrome 4B (MNGIE type) MIM#613662; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE) MIM#607459; Progressive external ophthalmoplegia, autosomal recessive 1 MIM#258450; Progressive external ophthalmoplegia, autosomal dominant 1, MIM# 157640 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1596 | POLG | Zornitza Stark reviewed gene: POLG: Rating: RED; Mode of pathogenicity: None; Publications: ; Phenotypes: Mitochondrial DNA depletion syndrome 4A (Alpers type) MIM#203700, Mitochondrial DNA depletion syndrome 4B (MNGIE type) MIM#613662, Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE) MIM#607459, Progressive external ophthalmoplegia, autosomal recessive 1 MIM#258450, Progressive external ophthalmoplegia, autosomal dominant 1, MIM# 157640; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.1425 | RYR1 |
Zornitza Stark changed review comment from: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). For review.; to: Well established association with susceptibility to malignant hyperthermia. However, variants in this gene also cause a range of muscular phenotypes, for which there is no specific treatment. Association with malignant hyperthermia is rated 'strongly actionable' in children by ClinGen. MH susceptibility (MHS) is a pharmacogenetic skeletal muscle disorder where exposure to certain volatile anesthetics (i.e., desflurane, enflurane, halothane, isoflurane, sevoflurane), either alone or with a depolarizing muscle relaxant (succinylcholine), may trigger uncontrolled skeletal muscle hypermetabolism. An MH episode may begin with hypercapnia, rapidly rising end-tidal CO2, and tachycardia followed by hyperthermia. Additional symptoms may include acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis and subsequent increased creatine kinase, hyperkalemia with a risk for cardiac arrhythmia or even arrest, and myoglobinuria with a risk for renal failure. There is mounting evidence that some individuals with MHS may also develop episodes triggered by non-anesthetic conditions such as heat and/or exercise. These non-anesthetic-induced episodes, often called MH-like syndrome, may manifest as exertional rhabdomyolysis (ER). Surgical management recommendations include preparation of the anesthesia workstation to reduce or prevent exposure to triggering anesthetics (e.g., remove vaporizers from machine and replace all disposables), vigilant monitoring for signs and symptoms of MH during perioperative period, and close observation and monitoring postoperatively. MHS patients should carry identification of their susceptibility and inform those responsible for their care of their MH status. Do not use the following MH triggering drugs for MHS patients: inhaled general anesthetics (desflurane, enflurane, halothane, isoflurane, sevoflurane) and depolarizing muscle relaxants (succinylcholine). |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.914 | ENG |
Zornitza Stark changed review comment from: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). For review.; to: Well established gene disease association. Clingen: strong actionability in adults Although HHT is a developmental disorder and infants are occasionally severely affected, in most people the features are age-dependent and the diagnosis is not suspected until adolescence or later. The average age of onset for epistaxis is 12 years, with 50-80% of patients affected before the age of 20 and 78-96% developing it eventually. Most patients report the appearance of telangiectasia of the mouth, face, or hands 5-30 years after the onset of nose bleeds, most commonly during the third decade. GI bleeding, when present, usually presents in the 5th or 6th decades of life. Patients rarely develop significant GI bleeding before 40 years of age. Women are affected with GI bleeding in a ratio of 2-3:1. AVMs of the brain are typically present at birth, whereas those in the lung and liver typically develop over time. Hemorrhage is often the presenting symptom of cerebral AVMs, while visceral AVMs may cause transient ischemic attacks, embolic stroke, and cerebral or other abscesses. Hepatic AVMs can present as high-output heart failure, portal hypertension, or biliary disease. However, screening guidelines recommend screening for cerebral AVMs in first 6 months of life or at diagnosis (MRI). Management guidelines also suggest screening in asymptomatic children for pulmonary AVMs, PMID 32894695. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.664 | ETFB |
Zornitza Stark changed review comment from: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis; to: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis Predominantly neonatal onset. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.523 | CPS1 | John Christodoulou reviewed gene: CPS1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: neonatal hyperammonaemia and subsequent recurrent episodes; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.274 | ETFA |
Zornitza Stark changed review comment from: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates, D,L-3-hydroxybutyrate Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis; to: Well established gene-disease association. Glutaric aciduria II (GA2) is an autosomal recessively inherited disorder of fatty acid, amino acid, and choline metabolism. It differs from GA I in that multiple acyl-CoA dehydrogenase deficiencies result in large excretion not only of glutaric acid, but also of lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. The heterogeneous clinical features of MADD fall into 3 classes: a neonatal-onset form with congenital anomalies (type I), a neonatal-onset form without congenital anomalies (type II), and a late-onset form (type III). The neonatal-onset forms are usually fatal and are characterized by severe nonketotic hypoglycemia, metabolic acidosis, multisystem involvement, and excretion of large amounts of fatty acid- and amino acid-derived metabolites. Symptoms and age at presentation of late-onset MADD are highly variable and characterized by recurrent episodes of lethargy, vomiting, hypoglycemia, metabolic acidosis, and hepatomegaly often preceded by metabolic stress. Muscle involvement in the form of pain, weakness, and lipid storage myopathy also occurs. The organic aciduria in those with the late-onset form of MADD is often intermittent and only evident during periods of illness or catabolic stress. Treatment: riboflavin, carnitine, glycine, Coenzyme Q10 supplementation, fat restriction, avoidance of fasting, and a diet rich in carbohydrates, D,L-3-hydroxybutyrate (PMID 31904027) Non-genetic confirmatory tests: plasma acylcarnitine profile, urine organic acid analysis |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.271 | HADHA |
Zornitza Stark changed review comment from: Well established gene-disease association. Clinical presentation is characterised by early-onset cardiomyopathy, hypoglycaemia, neuropathy, and pigmentary retinopathy, and sudden death Treatment: IV glucose during acute episodes, avoid fasting, carnitine, restrict LCFA, bezafibrate, triheptanoin; to: Well established gene-disease association. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death, infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy. Treatment: IV glucose during acute episodes, avoid fasting, carnitine, restrict LCFA, bezafibrate, triheptanoin |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.0 | DHCR24 |
Zornitza Stark gene: DHCR24 was added gene: DHCR24 was added to gNBS. Sources: Expert Review Red,BabySeq Category C gene Mode of inheritance for gene: DHCR24 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: DHCR24 were set to Desmosterolosis |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: BabyScreen+ v0.0 | DES |
Zornitza Stark gene: DES was added gene: DES was added to gNBS. Sources: BabySeq Category B gene,Expert Review Amber,BabySeq Category A gene Mode of inheritance for gene: DES was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: DES were set to Myopathy, myofibrillar; Cardiomyopathy, dilated |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||