Patient2: Female, 5.5yo

CasePresentingHPOs: HP:0002572, HP:0001259, HP:0003648, HP:0002919 (episodic vomiting, coma, lacticaciduria, ketonuria)

HPOsFreeText: chronic intermittent IVA, treated with a vegetarian diet and L-carnitine supplements, abnormal excretion of isovalerate metabolites, elevation of isovaleryl glycine in urine, C5-carnitine = 16 µmol/l, birth weight = 2kg, hospitalized at 2yo for vomiting and acidosis. At physical exam at 5.5yo, weight = 18kg, height = 103cm, IQ = 92, and unremarkable systemic examination

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 4mo at onset, 13mo at diagnosis via clinical presentation, consanguineous family, full-term delivery via Caesarean section due to failure of propagation

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.1207T>A

CAID: CA391724509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724509

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

Variant 1: NM_002225.3:c.1207T>A

Variant 2: NM_002225.4(IVD):c.863C>T

VariantEvidence: This variant is located in the turn region next to the alpha helix where hydrogen bonding is favorable, this location along with the presentation of severe phenotypes and biochemical profiles in the patients harboring these variants suggests a genotype-phenotype correlation (fig. 4)

Patient6: Male, 8yo

CasePresentingHPOs: HP:0002572 (episodic vomiting)

HPOsFreeText: chronic intermittent IVA, 3 monthly attacks of cyclic vomiting, treated with IVA special formula, elevated isovalerylglycine, C5-carnitine = 9.06 µmol/l

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 6mo, diagnosis at 72mo via clinical presentation, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3(IVD):c.465+2T>C

ClinVar: 94055, https://www.ncbi.nlm.nih.gov/clinvar/variation/94055/

gnomAD: 0.00001991, https://gnomad.broadinstitute.org/variant/15-40702998-T-C

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

Patient3: Female, 4.5yo, Family B (fig. 2)

CasePresentingHPOs: HP:0001733 (pancreatitis)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula and vegetarian diet, stopped formula at 2yo and remained on vegetarian diet. Urinary organic acid analysis showed elevated lactic acid, 3-hydroxy-isovaleric acid, and isovalerylglycine, C5-carnitine = 10.8 µmol/l, fluctuating levels of serum ammonia which were eventually normalized with oral sodium benzoate treatment, admitted to hospital 2 times for gastroenteritis with metabolic acidosis and then for recurrent vomiting due to acute pancreatitis. sat unsupported at 6mo, walked and spoke first word at 12mo. As last physical, height = 105cm, weight = 18kg, and had unremarkable neurologic, chest, cardiovascular, and abdominal exams

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at birth via NBS, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.ins386T (p.Tyr129fs) no ClinVar or CAID

Variant2: NM_002225.3(IVD):c.732C>T (p.Asp244=)

ClinVar: 94057, https://www.ncbi.nlm.nih.gov/clinvar/variation/94057/

gnomAD: n/a

Variant3: 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

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

VariantEvidence: This variant is located in the coil region of the protein where hydrogen bonding is limited, thus the variant would not have significant effects on bonding. This along with the mild phenotype in Patient 5 suggests a mild genotype-phenotype correlation for this variant

Patient8: Male, 6yo, Family C (fig. 2)

CasePresentingHPOs: HP:0000486, HP:0000651 (squint, diplopia)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula and oral L-carnitine, elevated isovalerylglycine, C5-carnitine = 6.8 µmol/l, normal development for age, weight = 128cm, weight = 28kg, normal chest, cardiovascular, and abdominal exams

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3do via NBS, consanguineous family, family history and multiple sibling deaths

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3:c.1207T>A

CAID: CA391724509, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724509

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

Patient4: Male, 2.5yo

CasePresentingHPOs: HP:0002033, HP:0001254, HP:0001987, HP:0001873, HP:0002013 (poor sucking, lethargy, hyperammonaemia, thrombocytopenia, vomiting)

HPOsFreeText: acute neonatal IVA, treated with IVA special formula along with sodium benzoate and glycine (benzoate and glycine discontinued after 1yr), elevated isovalerylglycine, C5-carnitine = 17.4 µmol/l, birth weight = 3kg, able to sit at 6mo, walked at 13mo, began to babble at 17mo, did not have bladder/bowel control until 2.5yo, current weight = 14kg, current height = 86.5cm

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: symptom onset at 5do, diagnosis at 30do via clinical presentation, consanguineous family

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.863C>T (p.Ala288Val) listed in paper as c.872C>T (p.Ala291Val)

ClinVar: 281076, https://www.ncbi.nlm.nih.gov/clinvar/variation/281076/

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

Patient1: Male, 4yo, Twin A, Family A (fig. 2)

CasePresentingHPOs:

HPOsFreeText: acute neonatal IVA, treated with IVA special formula, elevated isovalerylglycine in urine organic acids, C5-carnitine = 6.15 µmol/l, at 2yo stopped formula and switched to vegetarian diet with L-carnitine supplements, admitted every 3-4mo due to metabolic crisis, at 4yo began formula again along with vegetarian diet and L-carnitine supplements, sat alone at 6mo, walked alone at 1yo, spoke first word at 1yo, unremarkable systemic examination at 4yo

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3 days old via NBS (positive family history and 3 sibling deaths), consanguineous family

CasePMIDs: PMID: 24516753

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as c.1193G>A (p.R398Q)

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

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

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

Patient3: Female, 22yo

CasePresentingHPOs: HP:0001249 (intellectual disability)

HPOsFreeText: Blood C5-carnitine (μM) = 14.27, under a protein restricted diet with carnitine and glycine supplementation

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: diagnosed at 3yo after improper treatment

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.1007G>A (p.Cys309Tyr) listed in paper as (p.Cys307Tyr)

CAID: CA391722967, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391722967

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient5-2 Female, 1yo, sibling to patient 5-1

CasePresentingHPOs:

HPOsFreeText: Blood C5-carnitine (μM) = 13.47, under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2mo and asymptomatic at diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.347C>T (p.Ser89Phe) listed in paper as (p.Ser87Phe)

CAID: CA391716394, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716394

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient1: Male, 6yo

CasePresentingHPOs:

HPOsFreeText: Blood C5-carnitine (μM) = 18.96, under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 10days old and asymptomatic at diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.3:c.386A>G (p.Tyr99Cys) listed in paper as (p.His100Arg)

CAID: CA391716511, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716511

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient5-1: Female, 2.5yo, sibling to patient 5-2

CasePresentingHPOs:

HPOsFreeText: under a protein restricted diet with carnitine and glycine supplementation, normal development

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: 2mo diagnosis

CasePMIDs:

CasePreviousTesting: Blood amino acids and acylcarnitine analyzed with ESI-MS/MS, urine organic acid analysis with GC/MS

GroupMethod1: PCR (primers in table 2)

GroupMethod2: Direct sequencing

CaseGenotypingMethod: genomic DNA extracted from peripheral blood leukocytes, IVD exons amplified via PCR, then products were purified and underwent direct sequencing for variant analysis

Variant1: NM_002225.4:c.347C>T (p.Ser89Phe) listed in paper as (p.Ser87Phe)

CAID: CA391716394, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716394

gnomAD: n/a

Variant2: NM_002225.4(IVD):c.1199A>G (p.Tyr400Cys) listed in paper as (p.Tyr371Cys)

ClinVar: 371390, https://www.ncbi.nlm.nih.gov/clinvar/variation/371390/

gnomAD: n/a

Patient14: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_002225.3:c.125T>C

CAID: CA391743774, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391743774

gnomAD: n/a

Variant2: IVS2-1G>C no ClinVar or CAID

Patient17: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_001159508.1:c.943A>C

CAID: CA391723118, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391723118

gnomAD: n/a

Variant2: IVS3+5G>T no ClinVar or CAID

Patient11: 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_001354598.2:c.868G>A

CAID: CA391720951, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391720951

gnomAD: n/a

Patient10: 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_002225.4:c.436A>G

CAID: CA391716744, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391716744

**In ClinVar as: NM_002225.3(IVD):c.445A>G (p.Lys149Glu), https://www.ncbi.nlm.nih.gov/clinvar/variation/553403/

gnomAD: n/a

Patient16: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_001159508.1:c.149G>C (p.Arg50Thr) listed in paper as (p.Arg21Pro)

CAID: CA391743853, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391743853

gnomAD: n/a

Variant2: NM_002225.4:c.851G>A

CAID: CA7480763, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA7480763

**In ClinVar as: NM_002225.3(IVD):c.860G>A (p.Arg287Gln), https://www.ncbi.nlm.nih.gov/clinvar/variation/555453/ **

gnomAD: 0.00001770, http://gnomad.broadinstitute.org/variant/15-40707154-G-A

Patient18: Group 3

CasePresentingHPOs: same as group 3

CasePreviousTesting: same as group 3

CaseGenotypingMethod: same as group 3

Variant1: NM_002225.3:c.1136T>C (p.p.Ile349Thr) **listed in paper as (p.Phe350Ser)

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

gnomAD: n/a

Variant2: IVS3+5G>T no ClinVar or CAID

Patient8: 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.262G>T

CAID: CA391745812, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391745812

gnomAD: n/a

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

Patient10: Female, 11yo, sibling to patient 11

CasePresentingHPOs:

HPOsFreeText: intermittent isovaleric acidemia, C5 (DBS) = 15.7 μmol l−1, IVA incorp (%) = 7, IVG in urine mmol permol creatinine = 4376, pH = 7.35, Protein intake (g kg−1 per day) = 0.64, treated with carnitine and glycine 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 via family evaluation at 2 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3(IVD):c.884T>C (p.Leu295Pro)

ClinVar: 555464, https://www.ncbi.nlm.nih.gov/clinvar/variation/555464/

gnomAD: n/a

Variant2: NM_002225.3:c.1211A>G

CAID: CA391724518, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724518

gnomAD: n/a

Patient6: Female, 4yo

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 3.1 μmol l−1, IVG in urine mmol permol creatinine = 230, Ammonium (μmol l−1) = 56, pH = 7.37, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 104

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_002225.3:c.158G>A listed in ClinVar as: NM_002225.4(IVD):c.149G>A (p.Arg50His)

CAID: CA7480513, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA7480513

ClinVar: 370843, https://www.ncbi.nlm.nih.gov/clinvar/variation/370843/

gnomAD: 0.00002784, http://gnomad.broadinstitute.org/variant/15-40699841-G-A

Variant2: NM_002225.3(IVD):c.941C>T (p.Ala314Val)

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

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

Patient4: Female, 3yo sibling to patient 5

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 4.0 μmol l−1, IVA incorp (%) = 80, IVG in urine mmol permol creatinine = 242, Ammonium (μmol l−1) = 31, pH = 7.37, Protein intake (g kg−1 per day) = 1.5, treated with carnitine supplements, PDI/IQ in follow-up = 92

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, diagnosed at 26 days old

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.4(IVD):c.1205T>C (p.Ile402Thr)

ClinVar: 529433, https://www.ncbi.nlm.nih.gov/clinvar/variation/529433/

gnomAD: n/a

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: Male, 2yo

CasePresentingHPOs:

HPOsFreeText: Asymptomatic, C5 (DBS) = 1.6 μmol l−1, IVG in urine mmol permol creatinine = 272, IVA incorp (%) = 72, Ammonium (μmol l−1) = 51, pH = 7.39, Protein intake (g kg−1 per day) = 1.5, PDI/IQ in follow-up = 93

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 28 days, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.706G>A

CAID: CA268780419, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268780419

gnomAD: 0.00003187, http://gnomad.broadinstitute.org/variant/15-40705199-G-A

Patient14: Male, 24yo

CasePresentingHPOs: HP:0011968, HP:0002013, HP:0001944, HP:0001254, HP:0001259, HP:0001987, HP:0001941

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

HPOsFreeText: intermittent isovaleric acidemia, C5 (DBS) = 4.3 μmol l−1, IVA incorp (%) = 12, IVG in urine mmol permol creatinine = 16594, Ammonium (μmol l−1) = 126, pH = 7.17, Protein intake (g kg−1 per day) = 0.7, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 88

CaseNotHPOs:

NotHPOsFreeText: sweaty feet odor

CaseAddInfo: diagnosed via clinical findings at 1yo, hospitalized outside of detection period

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: c.1-?_c.295+? (Delexons 1–3) no ClinVar or CAID

Variant2: NM_002225.4(IVD):c.1184G>A (p.Arg395Gln) listed in paper as (p.Arg395His)

CAID: CA268781747, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA268781747

ClinVar: 529434, https://www.ncbi.nlm.nih.gov/clinvar/variation/529434/

gnomAD: 0.00001415, http://gnomad.broadinstitute.org/variant/15-40710365-G-A

Patient11: Female, 19yo, sibling to patient 10

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

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

HPOsFreeText: intermittent isovaleric acidemia, IVA incorp (%) = 13, IVG in urine mmol permol creatinine = 3488, Ammonium (μmol l−1) = 47 pH = 7.33, Protein intake (g kg−1 per day) = 1.0, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 85, sweaty feet odor

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: Diagnosed via clinical findings at 2yo

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant1: NM_002225.3(IVD):c.884T>C (p.Leu295Pro)

ClinVar: 555464, https://www.ncbi.nlm.nih.gov/clinvar/variation/555464/

gnomAD: n/a

Variant2: NM_002225.3:c.1211A>G

CAID: CA391724518, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA391724518

gnomAD: n/a

Patient13 Male, 9yo

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001259, HP:0001987

(poor feeding, lethargy, coma, hyperammonemia)

HPOsFreeText: acute isovaleric acidemia, C5 (DBS) = 16.3 μmol l−1, IVA incorp (%) = 5.5, IVG in urine mmol permol creatinine = 3352, Ammonium (μmol l−1) = 606, pH = 7.26, Protein intake (g kg−1 per day) = 0.8, treated with carnitine and glycine supplements, PDI/IQ in follow-up = 87, sweaty feet odor

CaseNotHPOs: HP:0002013, HP:0001944 (vomiting, dehydration)

NotHPOsFreeText:

CaseAddInfo: diagnosed via clinical findings at 20 days old, homozygous

CasePMIDs:

CasePreviousTesting: same as group

CaseGenotypingMethod: same as group

Variant: NM_002225.3:c.158G>C listed in clinvar as NM_002225.4(IVD):c.149G>C (p.Arg50Pro)

CAID: CA274129, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA274129

ClinVar: 188922, https://www.ncbi.nlm.nih.gov/clinvar/variation/188922/

gnomAD: 0.00001591, http://gnomad.broadinstitute.org/variant/15-40699841-G-C

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

Patient1: Male, 14 yo, Thai

CasePresentingHPOs: HP:0011968, HP:0001254, HP:0001250, HP:0001876, HP:0002919, HP:0001942, HP:0001987, HP:0002187, HP:0002300, HP:0002540, HP:0006846, HP:0002901, HP:0001510 (poor feeding, lethargy, seizures, pancytopenia, ketonuria, metabolic acidosis, hyperammonemia, profound mental retardation, inability to speak, inability to walk, acute encephalopathy, hypocalcemia, growth delay)

HPOsFreeText: acute neonatal IVA, hemoglobin = 10g/dL, WBC = 3370/mm^3, platelets = 27,000/mm^3, bicarbonate = 10mmol/L, anion gap = 36mmol/L, low serum calcium, ammonia = 420µmol/L, treated with total blood exchange, 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 = 515

CaseNotHPOs:

NotHPOsFreeText:

CaseAddInfo: non-consanguineous family, symptom onset at 7 days old, diagnosed at 2wks old

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_002225.3:c.1025A>G (p.Tyr342Cys) listed in paper as (p.Tyr371Cys)

CAID: CA7480839, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/allele?hgvs=NM_002225.3%3Ac.1025A%3EG

gnomAD: 0.000003977, https://gnomad.broadinstitute.org/variant/15-40708332-A-G

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