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| Genomic newborn screening: ICoNS v0.29 | KCNJ11 |
Val Jacquemin gene: KCNJ11 was added gene: KCNJ11 was added to Genomic newborn screening: ICoNS. Sources: Other Mode of inheritance for gene: KCNJ11 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: KCNJ11 were set to PMID: 28824061; PMID: 32027066; PMID: 21674179; PMID: 38226203; PMID: 26908106 Phenotypes for gene: KCNJ11 were set to Familial Hyperinsulinemic hypoglycemia 2 (CHI); MODY type 13; neonatale diabetes; DEND Syndrome Review for gene: KCNJ11 was set to RED Added comment: 1) Mutations in the KCNJ11 gene affect the ATP-sensitive potassium (KATP) channel in pancreatic β-cells, which links cellular metabolism to insulin secretion. When gain-of-function mutations occur, the KATP channel remains excessively open, preventing β-cell depolarization and impairing insulin release; this mechanism causes monogenic diabetes that can present either as Neonatal diabetes or as MODY13 depending largely on mutation severity and age of onset. Heterozygous activating mutations in KCNJ11 were first shown to cause neonatal diabetes, demonstrating that increased KATP channel activity suppresses insulin secretion and leads to hyperglycemia (Shimomura & Maejima 2017). The most severe activating mutations can also affect neuronal KATP channels, leading to the syndromic form known as DEND syndrome, characterized by developmental delay, epilepsy, and neonatal diabetes. Because milder activating variants may allow partial insulin secretion, diabetes can appear later in life and be classified as MODY13, placing both conditions on a clinical spectrum of KATP channel overactivity (De Franco et al. 2020). As activating mutations in KCNJ11 can lead either to neonatal diabetes or to MODY13, genotype alone does not reliably predict the age of disease onset. MODY13 typically manifests much later in life; reported cases show onset ranging from approximately 9 to 28 years of age, with many patients developing diabetes during adolescence (Chen et al. 2023). Because gNBS programs generally target disorders that produce symptoms in early childhood (e.g., before about 5 years of age) and require early intervention, MODY13 falls outside the scope of these screening criteria. Consequently, detecting a KCNJ11 activating mutation in a newborn would not allow clinicians to determine whether the child will develop neonatal diabetes in infancy or a later-onset MODY13 phenotype. For this reason, neonatal diabetes cannot reliably be included as a standalone condition in gNBS based solely on KCNJ11 variants. In contrast, the opposite mechanism, loss-of-function mutations in KATP channel genes such as KCNJ11, causes Congenital hyperinsulinism (familial hyperinsulinemic hypoglycemia), where defective channels cannot open, leading to persistent β-cell depolarization and inappropriate insulin secretion even during hypoglycemia. Most severe KATP-related CHI cases follow an autosomal recessive inheritance pattern, although some mutations can act dominantly and produce milder phenotypes (Kapoor et al. 2011). When focusing specifically on autosomal recessive KCNJ11-related CHI, biallelic inactivating mutations disrupt KATP channel activity and typically result in severe neonatal hypoglycemia. From a screening perspective, CHI typically presents with symptomatic hypoglycemia very shortly after birth, meaning it is usually detected rapidly through clinical glucose monitoring, thereby limiting the added value of gNBS (Stanley, 2016). In their comparative analysis of genomic newborn sequencing initiatives, Thomas Minten and colleagues reported that the KCNJ11 gene is included in 17 of the 27 gNBS programs evaluated in the study. These programs include BabySeq, BabyDetect, BeginNGS, Early Check, the GUARDIAN study, NESTS (Newborn Sequencing in Genomic Medicine and Public Health), gnSTAR, the Chen et al. newborn sequencing cohort, the Wang et al. newborn sequencing study, the Yang et al. multicenter sequencing study, the PerkinElmer genomic newborn screening panel, the PerkinElmer GS program, the NeoExome panel, BabyScreen+, NeoSeq, the targeted panel described by Huang et al. (inborn disorders of neonates), and the sequencing pilot described by Jian et al. (WGS screening pilot). However, the analysis compares gene inclusion rather than specific target conditions, and it is therefore not always clear which disease associated with KCNJ11 (e.g., monogenic diabetes or congenital hyperinsulinism) is intended to be screened for in each program. 2) ClinGen curation The KCNJ11 gene has been curated by Clinical Genome Resource (ClinGen) for its role in monogenic diabetes. ClinGen has classified the association between KCNJ11 and KATP-channel–related diabetes as Definitive, based on strong genetic and experimental evidence. Pathogenic variants in KCNJ11 are well established causes of Neonatal diabetes and MODY13 through gain-of-function effects on the KATP channel. The gene is also associated with Congenital hyperinsulinism through loss-of-function variants. ClinGen curation therefore supports a strong gene–disease relationship for both monogenic diabetes and hyperinsulinism. 3) Treatability and evidence Clinical studies have demonstrated that a large proportion of individuals with KCNJ11-related neonatal diabetes can successfully switch from insulin injections to sulfonylureas, leading to improved glycemic control and quality of life (Pearson et al., 2006, New England Journal of Medicine). In addition to improving metabolic control, early treatment may also improve neurological outcomes in some patients with syndromic forms of the disease such as DEND syndrome. For CHI (caused by loss-of-function KATP mutations), treatment may include diazoxide therapy, which acts as a KATP channel opener, although many recessive KATP-channel cases are diazoxide-unresponsive and may require pancreatectomy. Early diagnosis is therefore clinically important to prevent severe hypoglycemia and neurological damage. 4) Impact of treatment The clinical impact of appropriate treatment can be substantial: KCNJ11 neonatal diabetes --> switch from insulin to oral sulfonylureas, improved glycemic control, reduced treatment burden, potential improvement in neurological symptoms when therapy is initiated early Congenital hyperinsulinism --> diazoxide or octreotide therapy may prevent hypoglycemia, early recognition prevents hypoglycemic brain injury 5) Issues with genomic screening Despite the strong gene–disease association and available treatments, several challenges exist for genomic newborn screening of KCNJ11. Phenotypic ambiguity --> same mutation type in KCNJ11 can cause neonatal diabetes or MODY13 which have different ages of onset Technical sequencing considerations --> from a sequencing perspective, KCNJ11 is technically straightforward to analyze: small gene, no pseudogenes, good coverage in both exome and genome sequencing Clinical detection without genomics --> for autosomal recessive KCNJ11-related congenital hyperinsulinism, symptoms usually appear shortly after birth with severe hypoglycemia. Because neonatal glucose levels are routinely monitored, many cases are detected rapidly through standard clinical care, limiting the additional value of genomic newborn screening. Neonatal diabetes presents with persistent hyperglycemia in infancy, often leading to rapid clinical investigation. Sources: Other |
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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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