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| Genomic newborn screening: ICoNS v0.16 | GLA |
Abigail Veldman gene: GLA was added gene: GLA was added to Genomic newborn screening: ICoNS. Sources: ClinGen,Literature Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Publications for gene: GLA were set to 28613767; 37259462 Phenotypes for gene: GLA were set to Fabry disease (MIM 301500); Fabry disease, cardiac variant (MIM 301500) Penetrance for gene: GLA were set to Complete Mode of pathogenicity for gene: GLA was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Added comment: Age of onset: Variable, Classic form 4-8 yrs, late-onset variants >25 yrs Specifically difficult to predict in females Treatment: - Agalsidase-β (Recombinant α-GAL) - Agalsidase-α (Recombinant α-GAL) - Migalastat (Binds reversibly to the active site of the amenable mutant of α-GAL) - Investigational therapies Effect of (early) treatment: There is no consensus when to start with ERT Penetrance: Prevalence: Prevalence in white male populations has been linked to Fabry disease in a wide range, approximately 1:17,000 to 1:117,000. Classic Fabry disease mutations are seen in approximately 1:22,000 to 1:40,000 males, and atypical presentations are associated with about 1:1000 to 1:3000 males and 1:6000 to 1:40,000 females. Although it is an under-diagnosed condition, the disease is seen in all racial and ethnic groups. (PMID: 28613767) Sources: ClinGen, Literature |
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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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