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| Genomic newborn screening: ICoNS v0.4 | TCN2 |
David Eckstein gene: TCN2 was added gene: TCN2 was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: TCN2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: TCN2 were set to PMID: 24305960 Phenotypes for gene: TCN2 were set to Transcobalamin II deficiency, MIM#275350 Penetrance for gene: TCN2 were set to Complete Review for gene: TCN2 was set to GREEN Added comment: Well established gene-disease association https://medlineplus.gov/genetics/condition/transcobalamin-deficiency/ Haploinsufficiency Score = 30 https://search.clinicalgenome.org/kb/gene-dosage/HGNC:11653 Transcobalamin II deficiency (TCN2D) is an autosomal recessive disorder with onset in early infancy characterized by failure to thrive, megaloblastic anemia, and pancytopenia. Other features include methylmalonic aciduria, recurrent infections, and vomiting and diarrhea. Treatment with cobalamin results in clinical improvement, but the untreated disorder may result in mental retardation and neurologic abnormalities or death (1). Diagnosis: Diagnosis is based on laboratory findings showing pancytopenia (or isolated megaloblastic anemia or combined anemia and leucopenia) and accumulation of homocysteine and methylmalonic acid. Methionine concentration may be reduced. Serum cobalamin levels are typically not low (most circulating cobalamin bound to haptocorrin). Reduction of unsaturated B12 binding capacity (test must be carried out before starting treatment with vitamin B12) and Holo- TC levels are observed. Diagnosis is confirmed by quantification of total transcobalamin in serum or plasma or by genetic screening of TCN2. Postnatal diagnosis may be achieved by screening newborn serum by tandem mass spectroscopy to detect the presence of C3-carnitines derived from methylmalonic acid. (Orphanet https://www.orpha.net/en/disease/detail/859#) Treatment: Multiple case reports indicate good therapeutic effects from Vitamin B12 administration (2, 3). The BNF recommends hydroxocobalamin vs cyanocobalamin for this lifelong treatment*. Orphanet indicates that (t)reatment of TC involves maintenance of a very high serum cobalamin concentration (1,000-10,000 pg/ml) by intramuscular (IM) administration of hydroxocobalamin. Oral treatment or treatment with cyanocobalamin instead of hydroxocobalamin may result in poorer outcomes. Treatment with IM hydroxocobalamin at least once a week is recommended, with monitoring of biochemical and hematological parameters to ensure that treatment is effective. Follow-up into adulthood for asymptomatic children who continue to have abnormal metabolite excretion is recommended. (Orphanet https://www.orpha.net/en/disease/detail/859#) * this was cited in a BMJ article https://www.bmj.com/content/349/bmj.g5389.full but I can’t access the BNF to provide a direct citation. Included in BabyScreen+, BeginNGS, Guardian, Generation, EarlyCheck Panels with this gene • Bone Marrow Failure • Mendeliome • Combined Immunodeficiency • Intellectual disability syndromic and non-syndromic • Mackenzie's Mission_Reproductive Carrier Screening • Red cell disorders • Fetal anomalies • Prepair 1000+ • Genomic newborn screening: BabyScreen+ • Prepair 500+ • Vitamin metabolism disorders • Genomic newborn screening: ICoNS Full citations 1. https://www.omim.org/entry/275350?search=%22transcobalamin%20ii%20deficiency%22&highlight=%22transcobalamin%20ii%20deficiency%22#8 2. Martino, F., Magenta, A., Troccoli, M.L. et al. Long-term outcome of a patient with Transcobalamin deficiency caused by the homozygous c.1115_1116delCA mutation in TCN2 gene: a case report. Ital J Pediatr 47, 54 (2021). https://doi.org/10.1186/s13052-021-01007-6 3. Trakadis YJ, Alfares A, Bodamer OA, Buyukavci M, Christodoulou J, Connor P, Glamuzina E, Gonzalez-Fernandez F, Bibi H, Echenne B, Manoli I, Mitchell J, Nordwall M, Prasad C, Scaglia F, Schiff M, Schrewe B, Touati G, Tchan MC, Varet B, Venditti CP, Zafeiriou D, Rupar CA, Rosenblatt DS, Watkins D, Braverman N. Update on transcobalamin deficiency: clinical presentation, treatment and outcome. J Inherit Metab Dis. 2014 May;37(3):461-73. doi: https://doi.org/10.1007/s10545-013-9664-5. Epub 2013 Dec 5. PMID: 24305960. Sources: Expert list |
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| Genomic newborn screening: ICoNS v0.4 | ALDH7A1 |
Katrina Stone changed review comment from: Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported. Despite seizure control most patients have developmental delay/Intellectual disability Confirmatory test: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated) Pipecolic acid Δ1-piperideine-6-carboxylate (Δ1-P6C) Intervention: Pyridoxine for seizure control. From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy Additional information Incidence: 1:65 000 to 1:250 000 live births Onset of seizures can be outside the neonatal period Consensus guideline: PMID: 33200442 Sources: Other; to: Well established gene disease association ClinGen: strong actionability in paediatric patients Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported. Despite seizure control most patients have developmental delay/Intellectual disability Non genetic confirmatory tests: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated) Pipecolic acid Δ1-piperideine-6-carboxylate (Δ1-P6C) Intervention: Pyridoxine for seizure control. From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy Additional information Incidence: 1:65 000 to 1:250 000 live births Onset of seizures can be outside the neonatal period Consensus guideline: PMID: 33200442 Included in: Sources: Other |
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| Genomic newborn screening: ICoNS v0.4 | ALDH7A1 |
Katrina Stone gene: ALDH7A1 was added gene: ALDH7A1 was added to Genomic newborn screening: ICoNS. Sources: Other Mode of inheritance for gene: ALDH7A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ALDH7A1 were set to PMID: 20301659; 33200442 Phenotypes for gene: ALDH7A1 were set to Epilepsy, early-onset, 4, vitamin B6-dependent Penetrance for gene: ALDH7A1 were set to Complete Review for gene: ALDH7A1 was set to GREEN Added comment: Summary: classic presentation neonatal onset seizures which respond to pyridoxine but are not well controlled with antiepileptics. Later onset of seizures has been reported. Despite seizure control most patients have developmental delay/Intellectual disability Confirmatory test: alpha-aminoadipic semialdehyde (α-AASA) in urine and/or plasma (elevated) Pipecolic acid Δ1-piperideine-6-carboxylate (Δ1-P6C) Intervention: Pyridoxine for seizure control. From consensus guideline: To improve outcome, a lysine-restricted diet and competitive inhibition of lysine transport through the use of pharmacologic doses of arginine have been recommended as an adjunct therapy Additional information Incidence: 1:65 000 to 1:250 000 live births Onset of seizures can be outside the neonatal period Consensus guideline: PMID: 33200442 Sources: Other |
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| Genomic newborn screening: ICoNS v0.4 | AK2 |
Lilian Downie gene: AK2 was added gene: AK2 was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: AK2 was set to BIALLELIC, autosomal or pseudoautosomal |
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| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark Deleted their review | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark commented on gene: ACADM | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark Marked gene: ACADM as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark Gene: acadm has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark Classified gene: ACADM as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.3 | ACADM | Zornitza Stark Gene: acadm has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.2 | ACADVL |
Lilian Downie gene: ACADVL was added gene: ACADVL was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: ACADVL was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: ACADVL were set to PMID: 20301763; 32885845; 31372341 Phenotypes for gene: ACADVL were set to VLCAD deficiency MIM#201475 Review for gene: ACADVL was set to GREEN Added comment: Well established gene-disease association. VLCAD deficiency can be classified clinically into 3 forms: a severe early-onset form with high incidence of cardiomyopathy and high mortality; an intermediate form with childhood onset, usually with hypoketotic hypoglycemia and more favorable outcome; and an adult-onset, myopathic form with isolated skeletal muscle involvement, rhabdomyolysis, and myoglobinuria after exercise or fasting. - Severe disease is associated with no residual enzyme activity, often resulting from null variants. Approximately 81% of pathogenic truncating variants in ACADVL are associated with the severe early-onset form [Andresen et al 1999]. - A specific homozygous missense pathogenic variant (c.709T>C;p.Cys237Arg) leading to low long-chain fatty acid oxidation flux may also be associated with cardiac disease [Diekman et al 2015]. - Milder childhood and adult forms are often associated with residual enzyme activity. The common p.Val283Ala variant, in both homozygous and compound heterozygous genotypes, is typically associated with the non-cardiac phenotypes [Spiekerkoetter et al 2009, Diekman et al 2015, Miller et al 2015]. Treatment: avoid fasting, carnitine, restrict LCFA, bezafibrate, triheptanoin On BabyScreen+, BabySeq, BeginNGS, Guardian, Generation and EarlyCheck Sources: Expert list |
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| Genomic newborn screening: ICoNS v0.1 | ACADM |
Lilian Downie gene: ACADM was added gene: ACADM was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: ACADM was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: ACADM were set to Acyl-CoA dehydrogenase, medium chain, deficiency of MIM# 201450 Review for gene: ACADM was set to GREEN Added comment: Well established gene-disease association. Inherited deficiency of medium-chain acyl-CoA dehydrogenase is characterized by intolerance to prolonged fasting, recurrent episodes of hypoglycemic coma with medium-chain dicarboxylic aciduria, impaired ketogenesis, and low plasma and tissue carnitine levels. Can be severe, potentially fatal. Typical presentation is between 3 and 24 months. More than 98% of cases of MCAD deficiency have a pathogenic variant in ACADM, with the c.985A>G variant accounting for between 56-91% of cases. Treatment: management plan to avoid fasting. ClinGen: Strong Actionability in paediatric patients. Non-genetic confirmatory tests: Urine acylglycine analysis Included in BabyScreen+, BabySeq, BeginNGS, Guardian, Generation, EarlyCheck Sources: Expert list |
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| Genomic newborn screening: ICoNS v0.0 | Zornitza Stark Added Panel Genomic newborn screening: ICoNS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||