Patient8: Male, 2yo, sibling to patient 9

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 6.4 μmol l−1, Ammonium (μmol l−1) = 30, pH = 7.36, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 108

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS at 11 days old, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.941C>G

CAID: CA391721562, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391721562

gnomAD: n/a

Patient15: Female, 15yo

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001941

(poor feeding, vomiting, dehydration, acidosis)

HPOsFreeText: intermittent isovaleric acidemia, C5 (DBS) = 7.8 μmol l−1, IVA incorp (%) = 4.9, IVG in urine mmol permol creatinine = 4653, Ammonium (μmol l−1) = 28, pH = 7.18, Protein intake (g kg−1 per day) = 0.8, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 92

CaseNotHPOs: HP:0001254, HP:0001259 (lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: diagnosed via clinical findings at 6yo, hospitalized outside of detection period

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group, nucleotide changes detected in homozygosity in mRNA

Variant1: NM_002225.3:c.1099T>C

CAID: CA391723803, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391723803

gnomAD: n/a

Variant2: c.1-?_c.295+? (Delexons 1–3) no ClinVar or CAID

Patient9: Female, 3yo, sibling to patient 8

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 3.5 μmol l−1, Ammonium (μmol l−1) = 32, pH = 7.34, Protein intake (g kg−1 per day) = 1.8, PDI/IQ in follow-up = 95

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed via family evaluation at 3yo, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.941C>G

CAID: CA391721562, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391721562

gnomAD: n/a

Patient5: Male, 11mo, sibling to patient 4

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 6.0 μmol l−1, IVA incorp (%) = 64, IVG in urine mmol permol creatinine = 955, Ammonium (μmol l−1) = 65, pH = 7.41, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 85

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS at 10 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_001159508.1:c.1214T>C

CAID: CA268781818, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781818

gnomAD: 0.000003977, http://gnomad.broadinstitute.org/variant/15-40710485-T-C

Variant2: NM_001159508.1:c.500T>C

CAID: CA391717541, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391717541

gnomAD: n/a

Patient5: Male, 11mo, sibling to patient 4

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 6.0 μmol l−1, IVA incorp (%) = 64, IVG in urine mmol permol creatinine = 955, Ammonium (μmol l−1) = 65, pH = 7.41, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 85

CaseNotHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259

(poor feeding, vomiting, dehydration, lethargy, coma)

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: Diagnosed with NBS at 10 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_001159508.1:c.1214T>C

CAID: CA268781818, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781818

gnomAD: 0.000003977, http://gnomad.broadinstitute.org/variant/15-40710485-T-C

Variant2: NM_001159508.1:c.500T>C

CAID: CA391717541, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391717541

gnomAD: n/a

Patient7: Female, 1.9yo

CasePresentingHPOs: HP:0001254, HP:0011968, HP:0001298, HP:0001259, HP:0007021 (lethargy, poor feeding, encephalopathy, coma, pain insensitivity)

HPOsFreeText: acute neonatal IVA, convulsions, treated with IVA special formula along with L-carnitine and glycine supplements, elevated isovalerylglycine, C5-carnitine = 2.45 µmol/l, weight = 11kg, height = 90cm, currently meeting normal milestones and has normal neurological examination

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 3do, diagnosis at 10do via clinical presentation, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.1136T>C

CAID: CA391723904, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391723904

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient5: Male, 7yo

CasePresentingHPOs: HP:0002572, HP:0011968, HP:0011675, HP:0001254, HP:0011675, HP:0002616, HP:0001659 (episodic vomiting, poor feeding, lethargy, abnormal EKG, aortic root dilation, aortic regurgitation)

HPOsFreeText: chronic intermittent IVA, recurring hospitalization (every 3mo), abnormal urine odor, treated with vegetarian diet with L-carnitine, elevated isovalerylglycine, C5-carnitine = 4.6 µmol/l, birth weight = 3.5kg, at 7yo had an abnormal EKG and had subsequent abnormal ECHO, sat at 6mo, walked at 1.2yo, spoke first word at 1yo, current height = 128cm, current weight = 18kg

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 12mo, diagnosis at 60mo via clinical presentation, consanguineous family, older sister had poor sucking at birth and died at 7 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.749G>C

CAID: CA391718929, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391718929

gnomAD: n/a

Variant2: NC_000015.9:g.40699940T>C (NM_002225.4(IVD):c.234+14C=)

CAID: CA147572, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NC_000015.9%3Ag.40699940T%3EC

ClinVar: 94053, https://www.ncbi.nlm.nih.gov/clinvar/variation/94053/

gnomAD: 0.6830, https://gnomad.broadinstitute.org/variant/15-40699940-T-C

Patient9: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

Variant1: NM_002225.3(IVD):c.941C>T (p.Ala314Val) listed in paper as c.932C>T (p.Ala282Val)

ClinVar: 100060, https://www.ncbi.nlm.nih.gov/clinvar/variation/100060/

gnomAD: 0.0006507, http://gnomad.broadinstitute.org/variant/15-40707653-C-T

Variant2: NM_002225.3:c.359G>A

CAID: CA7480603, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA7480603

gnomAD: 0.000003977, http://gnomad.broadinstitute.org/variant/15-40702890-G-A

Patient12: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

Variant1: NM_002225.3(IVD):c.941C>T (p.Ala314Val) listed in paper as c.932C>T (p.Ala282Val)

ClinVar: 100060, https://www.ncbi.nlm.nih.gov/clinvar/variation/100060/

gnomAD: 0.0006507, http://gnomad.broadinstitute.org/variant/15-40707653-C-T

Variant2: NM_001159508.1:c.870_871insG

CAID: CA913184835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184835

gnomAD: n/a

Patient12: Group 2

CasePresentingHPOs: same as group 2

CasePreviousTesting: same as group 2

CaseGenotypingMethod: same as group 2

Variant1: NM_002225.3(IVD):c.941C>T (p.Ala314Val) listed in paper as c.932C>T (p.Ala282Val)

ClinVar: 100060, https://www.ncbi.nlm.nih.gov/clinvar/variation/100060/

gnomAD: 0.0006507, http://gnomad.broadinstitute.org/variant/15-40707653-C-T

Variant2: NM_001159508.1:c.870_871insG

CAID: CA913184835, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA913184835

gnomAD: n/a

Patient2: Female, 5yo, Thai

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0100806, HP:0001876, HP:0001290, HP:0001942, HP:0001987, HP:0002342 (poor feeding, lethargy, sepsis, pancytopenia, hypotonia, metabolic acidosis, hyperammonemia, moderate mental retardation)

HPOsFreeText: acute neonatal IVA, hemoglobin = 11g/dL, WBC = 3100/mm^3, platelets = 47,000/mm^3, sepsis treated with parenteral antibiotics and IV fluid, bicarbonate = 14mmol/L, anion gap = 18mmol/L, ammonia = 97µmol/L, began metabolic treatment at 14mo but was non-compliant, developmental quotient = 48, treated with low-protein diet and leucine-free formula (150–250mg/kg per day of l‐glycine, and 100mg/kg per day of l‐carnitine), urine isovalerylglycine = 153

CaseNotHPOs:

NotHPOsFreeText: ammo

CaseAddInfo: non-consanguineous family, diagnose with sepsis at 14 days old, lost to follow up at 5yo

CasePMIDs:

CasePreviousTesting: urine organic acid analysis with GC/MS (PMID: 27082169)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Genomic DNA extracted from peripheral blood, IVD coding exons and flanking introns amplified with PCR (primer in table 1), PCR products purified and sequenced with Big Dye Primer Cycle Sequencing Kit and ABI 210 Genetic Analyzer

Variant1: c.457–3_2CA>GG / no ClinVar or CAID

Variant2: NM_001354598.2:c.194C>G (p.Ala65Gly)

CAID: CA391744802, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391744802

gnomAD: n/a