FamilySA1: European

FamilyPresentingHPOs: HP:0001988, HP:0000825, HP:0001987 (Recurrent hypoglycemia, Hyperinsulinemic hypoglycemia, Hyperammonemia)

HPOsFreeText: N/A

FamilyNotHPOs: N/A

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Genomic DNA was prepared from all patients via peripheral blood leukocytes. The GLUD1 gene exons 1-13 and the flanking intronic regions were PCR-amplified and directly sequenced. All variants were confirmed via restriction enzyme analysis.

FamilyPreviousTesting: Leucine load test showed leucine sensitivity in some patients; Other causes of hypoglycemia were excluded (normal values for plasma cortisol, growth hormone, lactate, ammonia, amino acids, and urine organic acids)

FamilyAddInfo: N/A

Variant: NM_005271.5(GLUD1):c.820C>T (p.Arg274Cys)

ClinVar: 16128, https://www.ncbi.nlm.nih.gov/clinvar/variation/16128/

gnomAD: Not in gnomAD

Affected: 5

Segregations: 4

AddSegregationInfo: Pedigree in Figure 1a

CaseSA4P: Female, 12 months onset, European

CasePresentingHPOs: HP:0001988, HP:0000825, HP:0001987, HP:0002167 (Recurrent hypoglycemia, Hyperinsulinemic hypoglycemia, Hyperammonemia, Neurological speech impairment)

HPOsFreeText: N/A

CaseNotHPOs: N/A

NotHPOsFreeText: N/A

CaseAddInfo: Has mother with confirmed variant and similar phenotypes

CasePreviousTesting: Leucine load test showed leucine sensitivity; Protein/leucine restriction was effective at reducing symptoms

CaseGenotypingMethod: Genomic DNA was prepared from all patients via peripheral blood leukocytes. The GLUD1 gene exons 1-13 and the flanking intronic regions were PCR-amplified and directly sequenced. All variants were confirmed via restriction enzyme analysis. Additionally, paternity testing was performed by HLA typing and by southern blot analysis of DNA fragments as well as PCR analysis of STRs.

Variant: NM_005271.5(GLUD1):c.965G>A (p.Arg322His)

ClinVar: 16129, https://www.ncbi.nlm.nih.gov/clinvar/variation/16129/

gnomAD: Not in gnomAD

CaseSA1: Male, Serbia

CasePresentingHPOs: HP:0025190, HP:0001987, HP:0000825, HP:0001988, HP:0001252, HP:0025502, HP:0001263 (Generalized tonic-clonic seizure, Hyperammonemia, Hyperinsulinemic hypoglycemia, Recurrent hypoglycemia, Muscular hypotonia, Overweight, Global developmental delay)

HPOsFreeText: Born at term with a birth weight of 3850 g, birth length of 51 cm, and an Apgar score of 10

CaseNotHPOs: HP:0002353 (EEG abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy and non-consanguineous with no family history,

CasePreviousTesting: At 9 weeks blood glucose at 2.0 mmol/L, serum insulin level of 32.4 mIU/L, plasma ammonia level was of 277 μmol/L; No abnormalities in plasma amino acid levels nor in urinary organic acid concentrations

CaseGenotypingMethod: Genetic analysis was perfomed on the GLUD1 gene.

Variant: NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)

ClinVar: 16122, https://www.ncbi.nlm.nih.gov/clinvar/variation/16122/

gnomAD: Not in gnomAD

CaseSA1: Male, Serbia

CasePresentingHPOs: HP:0025190, HP:0001987, HP:0000825, HP:0001988, HP:0001252, HP:0025502, HP:0001263 (Generalized tonic-clonic seizure, Hyperammonemia, Hyperinsulinemic hypoglycemia, Recurrent hypoglycemia, Muscular hypotonia, Overweight, Global developmental delay)

HPOsFreeText: Born at term with a birth weight of 3850 g, birth length of 51 cm, and an Apgar score of 10

CaseNotHPOs: HP:0002353 (EEG abnormality)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy and non-consanguineous with no family history,

CasePreviousTesting: At 9 weeks blood glucose at 2.0 mmol/L, serum insulin level of 32.4 mIU/L, plasma ammonia level was of 277 μmol/L; No abnormalities in plasma amino acid levels nor in urinary organic acid concentrations

CaseGenotypingMethod: Genetic analysis was perfomed on the GLUD1 gene.

Variant: NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)

ClinVar: 16122, https://www.ncbi.nlm.nih.gov/clinvar/variation/16122/

gnomAD: Not in gnomAD