| Date | Panel | Item | Activity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Genomic newborn screening: ICoNS v0.27 | CYP21A2 |
Thomas Minten changed review comment from: On RUSP website CYP21A2 specifically mentioned as causative gene ClinGen: haploinsufficiency score of 30, high level of evidence Prevalence SW-CAH and SV-CAH: 1:11,000-1:14,000 Disease pathway: enzyme 21-hydroxylase produces cortisol and aldosterone -> important for hormone balance Presentation in neonatal onset, childhood: poor feeding, vomiting, weight loss or failure to thrive, excessive sleepiness or lethargy, irritability, and diarrhea. In females, ambiguous genitalia Treatment: Lifelong glucocorticoid replacement therapy (such as hydrocortisone) Inheritance: biallelic (recessive), autosomal or pseudoautosomal Current screening method for CAH: First tier: 17‑hydroxyprogesterone (17‑OHP) Second tier: steroid profiling/CYP21A2 genotyping Included (in 2024) in 16/27 gNBS programs, ranks 130 out of 4390 Included in BabyDetect, BabyScreen+,Generation, Beginnings, Puglia, Screen4Care, Nurture,… Not in Guardian, EarlyCheck Chen et al and several commercial panels Problem: Standard WGS methodologies face challenges in accurately detecting CYP21A2 variants because of this homology and population complexity. Therefore, by most programs is only used in conjunction with 17-OHP levels. Sources: Other; to: Gene causes adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency ClinGen: haploinsufficiency score of 30, high level of evidence Prevalence SW-CAH and SV-CAH: 1:11,000-1:14,000 Disease pathway: gene important for production of enzyme 21-hydroxylase, which in turn produces cortisol and aldosterone which is important for hormone balance Presentation in neonatal onset, childhood: poor feeding, vomiting, weight loss or failure to thrive, excessive sleepiness or lethargy, irritability, and diarrhea. In females, ambiguous genitalia. Treatment: Lifelong glucocorticoid replacement therapy (such as hydrocortisone) Inheritance: biallelic (recessive), autosomal or pseudoautosomal Current biochemical screening method for CAH is performed in most countries: First tier: 17‑hydroxyprogesterone (17‑OHP) Second tier: steroid profiling/CYP21A2 genotyping High genotype phenotype correlation as discussed in PMID 23359698 Included (in 2024) in 16/27 gNBS programs, ranks 130 out of 4390 Included in BabyDetect, BabyScreen+,Generation, Beginnings, Puglia, Screen4Care, Nurture,… Not in Guardian, EarlyCheck, Chen et al. and several commercial panels Problem: Standard WGS methodologies face challenges in accurately detecting CYP21A2 variants because of homology and population complexity. Therefore, by most gNBS programs the results in this gene are only used in conjunction with 17-OHP levels. Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.27 | CYP21A2 |
Thomas Minten gene: CYP21A2 was added gene: CYP21A2 was added to Genomic newborn screening: ICoNS. Sources: Other Mode of inheritance for gene: CYP21A2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CYP21A2 were set to CYP21A2 Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency Mode of pathogenicity for gene: CYP21A2 was set to Other Review for gene: CYP21A2 was set to GREEN Added comment: On RUSP website CYP21A2 specifically mentioned as causative gene ClinGen: haploinsufficiency score of 30, high level of evidence Prevalence SW-CAH and SV-CAH: 1:11,000-1:14,000 Disease pathway: enzyme 21-hydroxylase produces cortisol and aldosterone -> important for hormone balance Presentation in neonatal onset, childhood: poor feeding, vomiting, weight loss or failure to thrive, excessive sleepiness or lethargy, irritability, and diarrhea. In females, ambiguous genitalia Treatment: Lifelong glucocorticoid replacement therapy (such as hydrocortisone) Inheritance: biallelic (recessive), autosomal or pseudoautosomal Current screening method for CAH: First tier: 17‑hydroxyprogesterone (17‑OHP) Second tier: steroid profiling/CYP21A2 genotyping Included (in 2024) in 16/27 gNBS programs, ranks 130 out of 4390 Included in BabyDetect, BabyScreen+,Generation, Beginnings, Puglia, Screen4Care, Nurture,… Not in Guardian, EarlyCheck Chen et al and several commercial panels Problem: Standard WGS methodologies face challenges in accurately detecting CYP21A2 variants because of this homology and population complexity. Therefore, by most programs is only used in conjunction with 17-OHP levels. Sources: Other |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.27 | LHX3 | Zornitza Stark Marked gene: LHX3 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.27 | LHX3 | Zornitza Stark Gene: lhx3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.27 | LHX3 | Zornitza Stark Phenotypes for gene: LHX3 were changed from to Pituitary hormone deficiency, combined, 3 (MIM#221750) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.26 | LHX3 | Zornitza Stark Classified gene: LHX3 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.26 | LHX3 | Zornitza Stark Gene: lhx3 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.25 | LHX3 | Zornitza Stark reviewed gene: LHX3: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.25 | GALK1 | Zornitza Stark Marked gene: GALK1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.25 | GALK1 | Zornitza Stark Gene: galk1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.25 | GALK1 | Zornitza Stark Phenotypes for gene: GALK1 were changed from very early-onset cataract to Galactokinase deficiency with cataracts MIM#230200 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.24 | GALK1 | Zornitza Stark Publications for gene: GALK1 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.23 | GALK1 | Zornitza Stark Classified gene: GALK1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.23 | GALK1 | Zornitza Stark Gene: galk1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.22 | GALK1 | Zornitza Stark reviewed gene: GALK1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.22 | F9 | Zornitza Stark Marked gene: F9 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.22 | F9 | Zornitza Stark Gene: f9 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.22 | F9 | Zornitza Stark Phenotypes for gene: F9 were changed from Hemophilia B to Haemophilia B, MIM# 306900 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.21 | F9 | Zornitza Stark Publications for gene: F9 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.20 | F9 | Zornitza Stark Classified gene: F9 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.20 | F9 | Zornitza Stark Gene: f9 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.19 | MYH7 | Zornitza Stark Marked gene: MYH7 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.19 | MYH7 | Zornitza Stark Gene: myh7 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.19 | MYH7 | Zornitza Stark Mode of inheritance for gene: MYH7 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.18 | MYH7 | Zornitza Stark Mode of inheritance for gene: MYH7 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.17 | MYH7 | Zornitza Stark Classified gene: MYH7 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.17 | MYH7 | Zornitza Stark Gene: myh7 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | MYH7 | Zornitza Stark reviewed gene: MYH7: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | F9 | Zornitza Stark reviewed gene: F9: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: ; Mode of inheritance: None | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 |
François BOEMER changed review comment from: Development of cataracts is fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Disorder is included in the RUSP as a secondary condition. NBS could be performed by gNBS, or by quantifying total Galactose on DBS. Urinary galactitol is elevated in a majority of neonate patients. GALK1 is curated by ClinGen. Only SNPs variants are described in Clinvar, mainly in the coding or intronic-boundaries regions ; to: Development of cataracts is fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Disorder is included in the RUSP as a secondary condition. NBS could be performed by gNBS, or by quantifying total Galactose on DBS. Urinary galactitol is elevated in a majority of neonate patients. GALK1 is curated by ClinGen. Only SNPs variants (> 500) are described in Clinvar, mainly in the coding or intronic-boundaries regions |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | F9 |
Jorune Balciuniene changed review comment from: Well established gene-disease association. Mechanism: hemizygous loss of function variants in males, but heterozygous females may present with mild clinical symptoms due to nonrandom X-inactivation. Incidence: 1 per 25-30K males births with >40 % having severe disease. Clinical disease types: Severe hemophilia B: < 1% normal FIX level. Usually diagnosed during the first two years of life. Characterized by spontaneous bleedings if not treated. Moderate hemophilia B: 1-5% normal FIX levels. Prolonged bleeding after trauma, diagnosed before the age of 5. Mild hemophilia B: 5- 40% normal FIX levels. Typically, no spontaneous bleedings, not diagnosed until later in life. Pathogenic variants: >1300 pathogenic variants, mostly point mutations, but also partial and full gene deletions. Medical management informing pathogenic variants • Complete gene deletions or major rearrangements are associated with severe anaphylactic reactions upon FIX replacement therapy. High risk for developing FIX inhibitors (> 50 %). • Point mutations in promoter region (5'UTR) associated with Hemophilia B Leyden, characterized by developmental expression of FIX post puberty. At childhood, FIX levels are <1%, and increase with growth reaching up to 70% of normal levels. Anabolic steroids can help raise FIX levels. • Missense variants in the FIX propeptide sequence causing reduced affinity to vitamin- dependent carboxylase. These individuals have normal levels of FIX, but develop unexpected reduction of FIX upon administration of vitamin K antagonists (e.g. warfarin) Treatment: • Factor replacement therapy: Prophylaxis and early treatment • Non-factor therapies: available for patients >12 y of age. • Adeno-associated virus gene therapy: for adult males with <2% of FIX levels • Surveillance and Supportive care PMIDs: 16643212, 25851415, 3286010, 3416069, 35269902 https://www.cdc.gov/hemophilia/mutation-project/index.html; to: Well established gene-disease association. Mechanism: hemizygous loss of function variants in males, but heterozygous females may present with mild clinical symptoms due to nonrandom X-inactivation. Incidence: 1 per 25-30K males births with >40 % having severe disease. Clinical disease types: Severe hemophilia B: < 1% normal FIX level. Usually diagnosed during the first two years of life. Characterized by spontaneous bleedings if not treated. Moderate hemophilia B: 1-5% normal FIX levels. Prolonged bleeding after trauma, diagnosed before the age of 5. Mild hemophilia B: 5- 40% normal FIX levels. Typically, no spontaneous bleedings, not diagnosed until later in life. Pathogenic variants: >1300 pathogenic variants, mostly point mutations, but also partial and full gene deletions. Medical management informing pathogenic variants • Complete gene deletions or major rearrangements are associated with severe anaphylactic reactions upon FIX replacement therapy. High risk for developing FIX inhibitors (> 50 %). • Point mutations in promoter region (5'UTR) associated with Hemophilia B Leyden, characterized by developmental expression of FIX post puberty. At childhood, FIX levels are <1%, and increase with growth reaching up to 70% of normal levels. Anabolic steroids can help raise FIX levels. • Missense variants in the FIX propeptide sequence causing reduced affinity to vitamin-K dependent carboxylase. These individuals have normal levels of FIX, but develop unexpected reduction of FIX upon administration of vitamin K antagonists (e.g. warfarin) Treatment: • Factor replacement therapy: Prophylaxis and early treatment • Non-factor therapies: available for patients >12 y of age. • Adeno-associated virus gene therapy: for adult males with <2% of FIX levels • Surveillance and Supportive care PMIDs: 16643212, 25851415, 3286010, 3416069, 35269902 https://www.cdc.gov/hemophilia/mutation-project/index.html |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | LHX3 |
José Manuel González de Aledo Castillo gene: LHX3 was added gene: LHX3 was added to Genomic newborn screening: ICoNS. Sources: Literature Mode of inheritance for gene: LHX3 was set to BIALLELIC, autosomal or pseudoautosomal Added comment: LHX3 – Well-established gene–disease association Not yet scored by ClinGen, definitive in GenCC for non-acquired Combined Pituitary Hormone Deficiency type 3 (CPHD3). AR CPHD3 is characterized by multiple anterior pituitary hormone deficiencies, including growth hormone, TSH, LH/FSH, prolactin, and variably ACTH. Affected individuals often have restricted neck mobility due to cervical spine anomalies and sensorineural hearing loss. CPHD3 can be severe and potentially life-threatening in infancy, due to recurrent hypoglycemia, prolonged jaundice, and metabolic instability. Typical presentation is from the newborn period through early infancy, though some patients are diagnosed later in childhood due to growth failure or pubertal delay. The vast majority of clinically confirmed CPHD3 cases carry biallelic pathogenic variants in LHX3, primarily loss-of-function or homeodomain-disrupting missense variants. Recurrent pathogenic variants such as T194R, W224Ter, C74 and V205L have been reported. Treatment: Lifelong hormone replacement tailored to specific deficiencies (levothyroxine, growth hormone, hydrocortisone when needed, and sex steroids during adolescence). Management also includes audiologic support and evaluation of cervical spine stability. Non-genetic confirmatory tests available: Pituitary hormone profile (GH, TSH, PRL, LH/FSH, with surveillance for evolving ACTH deficiency), pituitary MRI showing anterior pituitary hypoplasia, audiology testing, and cervical spine imaging. Conventional newborn screening: indirect through CH screening (universal) Genomic newborn screening: included in BabyScreen+, Babyseq, BeginNGS, FirstSteps, Generation Study, NewbornsinSA, Puglia. Sources: Literature |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | F9 | Jorune Balciuniene reviewed gene: F9: Rating: GREEN; Mode of pathogenicity: None; Publications: 20301668, 32809627; Phenotypes: Hemophilia B; Mode of inheritance: X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males); Current diagnostic: yes | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 | François BOEMER edited their review of gene: GALK1: Changed phenotypes: Early-onset cataract | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 |
François BOEMER changed review comment from: Development of cataracts is fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Disorder is included in the RUSP as a secondary condition. NBS could be performed by gNBS, or quantifying total Galactose on DBS. Urinary galactitol is elevated in a majority of neonate patients.; to: Development of cataracts is fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Disorder is included in the RUSP as a secondary condition. NBS could be performed by gNBS, or by quantifying total Galactose on DBS. Urinary galactitol is elevated in a majority of neonate patients. GALK1 is curated by ClinGen. Only SNPs variants are described in Clinvar, mainly in the coding or intronic-boundaries regions |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 |
François BOEMER changed review comment from: Included in the RUSP as a secondary condition. Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Sources: Expert Review; to: Development of cataracts is fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Disorder is included in the RUSP as a secondary condition. NBS could be performed by gNBS, or quantifying total Galactose on DBS. Urinary galactitol is elevated in a majority of neonate patients. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 | François BOEMER edited their review of gene: GALK1: Changed publications: PMID: 32807972 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 |
François BOEMER changed review comment from: Included in the RUSP as a secondary condition. Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Sources: Expert Review; to: Included in the RUSP as a secondary condition. Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | GALK1 |
François BOEMER gene: GALK1 was added gene: GALK1 was added to Genomic newborn screening: ICoNS. Sources: Expert Review Mode of inheritance for gene: GALK1 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GALK1 were set to very early-onset cataract Penetrance for gene: GALK1 were set to Complete Review for gene: GALK1 was set to GREEN Added comment: Included in the RUSP as a secondary condition. Development of cataracts appears to be fully preventable if diagnosis is made early and a galactose-restricted diet is implemented and strictly followed. Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | MYH7 |
François BOEMER edited their review of gene: MYH7: Added comment: The natural history of MYH7-related cardiomyopathies shows considerable variation in age of onset. In the 2022 paper by de Frutos et al., only 9 of 115 reported cases developed symptoms before 10 years of age. Moreover, substantial phenotypic heterogeneity can occur among affected members of the same family. Consequently, within the BabyDetect project, the reporting criteria for MYH7 variants are restricted to cases in which two variants are identified—either in a homozygous state or as possible compound heterozygotes.; Set current diagnostic: yes |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | MYH7 |
François BOEMER gene: MYH7 was added gene: MYH7 was added to Genomic newborn screening: ICoNS. Sources: Expert Review Mode of inheritance for gene: MYH7 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: MYH7 were set to doi.org/10.1016/j.jacc.2022.07.023; doi.org/10.1038/gim.2017.218 Phenotypes for gene: MYH7 were set to Cardiomyopathy, dilated, 1S; Cardiomyopathy, hypertrophic, 1; Congenital myopathy 7A, myosin storage, autosomal dominant; Congenital myopathy 7B, myosin storage, autosomal recessive; Laing distal myopathy; Left ventricular noncompaction 5 Penetrance for gene: MYH7 were set to Complete Mode of pathogenicity for gene: MYH7 was set to Other Review for gene: MYH7 was set to GREEN Added comment: Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.16 | PAH |
Lilian Downie gene: PAH was added gene: PAH was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: PAH was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PAH were set to PMID: 39630157; 40378670 Phenotypes for gene: PAH were set to Phenylketonuria MIM#261600 Review for gene: PAH was set to GREEN Added comment: Definitive gene disease association Definitive for actionability in childhood Included in traditional newborn screening in all jurisdictions Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.15 | ALDH7A1 | Zornitza Stark Marked gene: ALDH7A1 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.15 | ALDH7A1 | Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.15 | ALDH7A1 | Zornitza Stark Phenotypes for gene: ALDH7A1 were changed from Epilepsy, early-onset, 4, vitamin B6-dependent to Epilepsy, pyridoxine-dependent, MIM#266100 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.14 | ALDH7A1 | Zornitza Stark Classified gene: ALDH7A1 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.14 | ALDH7A1 | Zornitza Stark Gene: aldh7a1 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.13 | ALDH7A1 | Zornitza Stark reviewed gene: ALDH7A1: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Epilepsy, pyridoxine-dependent, MIM#266100; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.13 | GAMT | Zornitza Stark Marked gene: GAMT as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.13 | GAMT | Zornitza Stark Gene: gamt has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.13 | GAMT | Zornitza Stark Publications for gene: GAMT were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.12 | GAMT | Zornitza Stark Classified gene: GAMT as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.12 | GAMT | Zornitza Stark Gene: gamt has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.11 | GAMT | Zornitza Stark reviewed gene: GAMT: Rating: GREEN; Mode of pathogenicity: None; Publications: ; Phenotypes: Cerebral creatine deficiency syndrome 2, MIM#612736; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.11 | ABCC8 | Zornitza Stark Marked gene: ABCC8 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.11 | ABCC8 | Zornitza Stark Gene: abcc8 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.11 | ABCC8 | Zornitza Stark Phenotypes for gene: ABCC8 were changed from Diabetes mellitus, noninsulin-dependent MIM#125853 Diabetes mellitus, permanent neonatal 3 MIM# 618857 AD, AR Diabetes mellitus, transient neonatal 2 MIM#610374 Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450 AD, AR Hypoglycemia of infancy, leucine-sensitive MIM#240800 AD Maturity-onset diabetes of the young, type 12 MIM#621196 AD to Diabetes mellitus, permanent neonatal 3 MIM# 618857 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.10 | ABCC8 | Zornitza Stark Classified gene: ABCC8 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.10 | ABCC8 | Zornitza Stark Gene: abcc8 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.9 | ABCC8 | Zornitza Stark reviewed gene: ABCC8: Rating: AMBER; Mode of pathogenicity: None; Publications: ; Phenotypes: Diabetes mellitus, permanent neonatal 3 MIM# 618857; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.9 | ABCC8 |
Lilian Downie gene: ABCC8 was added gene: ABCC8 was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: ABCC8 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: ABCC8 were set to PMID: 20301620; 32027066; 20922570; 16885549 Phenotypes for gene: ABCC8 were set to Diabetes mellitus, noninsulin-dependent MIM#125853 Diabetes mellitus, permanent neonatal 3 MIM# 618857 AD, AR Diabetes mellitus, transient neonatal 2 MIM#610374 Hyperinsulinemic hypoglycemia, familial, 1 MIM#256450 AD, AR Hypoglycemia of infancy, leucine-sensitive MIM#240800 AD Maturity-onset diabetes of the young, type 12 MIM#621196 AD Review for gene: ABCC8 was set to GREEN Added comment: Gene-disease association: Curated by ClinGen: definitive for monogenic diabetes Moderate for pulmonary hypertension. LOF heterozygous variants cause hyperinsulinism and neonatal hypoglycemia. requires a paternal pathogenic variant and a somatic second hit on the maternal allele. There is no phenotype for an isolated maternal pathogenic variant. GoF missense variants cause neonatal diabetes mellitus: Clinical manifestations at diagnosis include intrauterine growth restriction (IUGR; a reflection of insulin deficiency in utero), hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and poor weight gain.: KATP channel unable to close in response to ATP, impairing insulin secretion Non-molecular confirmatory testing: yes For hyperinsulinaemic hypoglycaemia: glucose, insulin, free fatty acid levels For neonatal diabetes: glucose tolerance test, hemoglobin A1C, insulin level, glucose level NB Ashkenazi founder variants: NP_000343.2:p.Phe1387del or NM_000352.6:c.3989-9G>A. Finnish founder variants NP_000343.2:p.Val187Asp or NP_000343.2:p.Glu1506Lys. Treatment: as per rx-genes For hyperinsulinaemic hypoglycaemia: Diazoxide, somatostatin analogs, nifedipine, glucagon, IGF-1, glucocorticoids, growth hormone, pancreatic resection, mTOR inhibitors, GLP-1 receptor antagonists, sirolimus For neonatal diabetes: Insulin, glibenclamide (Sulfonylurea), oral pancreatic enzymes, Not included by GUARDIAN ?reason ?variable phenotypes, some are adult onset, would need to make variant level decisions on reporting Variable expression - variants can be inherited and cause T2DM in a parent Not included in newborn screening currently Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.8 | TCN2 | Lilian Downie Marked gene: TCN2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.8 | TCN2 | Lilian Downie Gene: tcn2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.8 | TCN2 | Lilian Downie Classified gene: TCN2 as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.8 | TCN2 |
Lilian Downie Added comment: Comment on list classification: Not on BabySeq 1 list, on other pilots. Detectable on TMS but ?not in standard NBS |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.8 | TCN2 | Lilian Downie Gene: tcn2 has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | GAMT | Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022, https://doi.org/10.1016/j.ymgme.2024.108362. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | GAMT | Judit Garcia edited their review of gene: GAMT: Changed publications: PMID: 36856349, PMID: 28055022, PMID: 28055022 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | GAMT |
Judit Garcia changed review comment from: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023. The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014. There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc. Only in RED in Cerebral Palsy, Fetal anomalies. Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship. There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine. There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; to: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023. The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014. There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc. Only in RED in Cerebral Palsy, Fetal anomalies. Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship. There is a biochemical test to confirm pathogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine. There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | GAMT |
Judit Garcia edited their review of gene: GAMT: Added comment: Broad review of CCDS biology/phenotypes including GAMT. Mulik et al., Children (Basel), 2023. The condition is treatable when identified early (creatine supplementation, dietary management). Treatment: Oral creatine monohydrate to replenish cerebral creatine plus arginine restriction and L-ornithine supplementation to reduce GAA; best outcomes with early initiation. https://www.ncbi.nlm.nih.gov/books/NBK3794/?utm_source=chatgpt.com; Stockler-Ipsiroglu et al., Mol Genet Metab, 2014. There is good evidence of GREEN in other panel of gens: Mendeliome, Genetic Epilepsy, Intellectual Disability, Dystonia – complex, Reproductive Carrier Screening, Metabolic Disorders, Newborn screening panels, etc. Only in RED in Cerebral Palsy, Fetal anomalies. Evidence sources: Expert Review Green, NHS GMS, Victorian Clinical Genetics Services, Australian Genomics Health Alliance Epilepsy Flagship. There is a biochemical test to confirm patogenicity of variants detected. Pathogenic variants: Increased Guanidinoacetic acid (GAA) in urine, plasma and dired blood spot; brain MRS with reduced creatine. There is a definitive gene–disease validity (ClinGen); use CCDS VCEP ACMG/AMP specifications for variant classification in clinical reporting.; Changed publications: PMID: 36856349, PMID: 28055022; Changed phenotypes: Creberal creatine deficiency syndrome 2 (MIM 612736), global developmental delay, intellectual disability, epilepsy, behavioral disturbance, movement disorder, markedly low brain creatine and elevated guanidinoacetate. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | GAMT |
Judit Garcia gene: GAMT was added gene: GAMT was added to Genomic newborn screening: ICoNS. Sources: Expert Review Mode of inheritance for gene: GAMT was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: GAMT were set to Creberal creatine deficiency syndrome 2 (MIM 612736) Penetrance for gene: GAMT were set to Complete Review for gene: GAMT was set to GREEN gene: GAMT was marked as current diagnostic Added comment: Sources: Expert Review |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | F9 |
Jorune Balciuniene gene: F9 was added gene: F9 was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: F9 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: F9 were set to Hemophilia B Penetrance for gene: F9 were set to Complete |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | CBS |
Zornitza Stark changed review comment from: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025. Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and subsequently upgraded. Therefore there is full consensus to include this gene in gNBS studies.; to: Discussed at ICoNS Gene List Subcommittee meeting on 22/08/2025. Originally excluded by BabyScreen+ study due to concerns about mappability especially on ES. On further assessment, issue is less pronounced on WGS and gene subsequently included in the study. Therefore there is full consensus to include this gene in gNBS studies. |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | CBS | Zornitza Stark Marked gene: CBS as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | CBS | Zornitza Stark Gene: cbs has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.7 | CBS | Zornitza Stark Publications for gene: CBS were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.6 | CBS | Zornitza Stark Classified gene: CBS as Green List (high evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.6 | CBS | Zornitza Stark Gene: cbs has been classified as Green List (High Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.5 | CBS | Zornitza Stark reviewed gene: CBS: Rating: GREEN; Mode of pathogenicity: None; Publications: 27778219; Phenotypes: Homocystinuria, B6-responsive and nonresponsive types MIM#236200; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.5 | CBS |
Lilian Downie gene: CBS was added gene: CBS was added to Genomic newborn screening: ICoNS. Sources: Expert list Mode of inheritance for gene: CBS was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: CBS were set to Homocystinuria, B6-responsive and nonresponsive types MIM#236200 Added comment: Well established gene-disease association. Multi-system disorder, onset can be in infancy - highly variable. In general, individuals appear normal at birth but have a progressive disease course if untreated. Clinical features typically manifest in the first or second decade of life. Intellectual disability may be the first recognizable sign and may present as developmental delay after the first to second year of life. Myopia typically occurs after age one with the majority of untreated individuals developing ectopia lentis by age 8. Roughly half of patients show signs of osteoporosis by their teens. Cerebrovascular events typically manifest during young adulthood, though they have been reported earlier. Thromboembolism is the major cause of early death and morbidity. Among B₆-responsive individuals, a vascular event in adolescence or adulthood is often the presenting feature. Homozygous for the p.I278T can be asymptomatic throughout life or have isolated thromboembolism. Treatment: vitamin B6 (pyridoxine), methionine-restricted diet, folate, vitamin B12, betaine. Management guidelines PMID 27778219. Non-genetic confirmatory testing: plasma total homocysteine and plasma amino acids Paediatric actionable gene by ClinGen. Sources: Expert list |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.4 | AK2 | Lilian Downie reviewed gene: AK2: Rating: AMBER; Mode of pathogenicity: None; Publications: 19043416, 19043417, 40654267; Phenotypes: Reticular dysgenesis MIM#267500; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| 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 |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Genomic newborn screening: ICoNS v0.0 | Zornitza Stark Added Panel Genomic newborn screening: ICoNS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||