CasePt15 Male, 2mo report, Italian

CasePresentingHPOs HP:0002789, HP:0001950, HP:0001987, HP:0003572, HP:0003217 (Tachpnea, Respiratory alkalosis, Hyperammonemia, Low plasma citrulline, High plasma glutamine)

HPOsFreeText Tachypnoeic, respiratory alkalosis(36h), coma(48h), hyperammonemia, low citrulline, elevated glutamine

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(6[normal 16-40μmol/l]), glutamine(1824[normal 530–913μmol/l]) and ammonia(1300[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.1145C>T (p.Pro382Leu), 2. NM_001875.4:c.2891G>A (p.Gly964Asp) compound heterozygous

ClinVar n/a

CAID 1. CA2086267, CA64723299

gnomAD 1. 0.00007189(European (Non-Finnish)), 0.00003664(Total), 2. n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 21120950

CasePt12 Female, 2do death, Italian

CasePresentingHPOs HP:0001290, HP:0002098, HP:0001987, HP:0003572, HP:0003217 (Hypotonia, Respiratory distress, Hyperammonemia, Low plasma citrulline, High plasma glutamine

HPOsFreeText Hypotonia and respiratory stress at birth, hyperammonemia, low citrulline, elevated glutamine

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(0[normal 16-40μmol/l]), glutamine(2300[normal 530–913μmol/l]) and ammonia(1831[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant NM_001875.4:c.1981G>C (p.Gly661Arg) homozygous

ClinVar n/a

CAID CA350438282

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs n/a

CasePt11 male, 3yo report, Italian

CasePresentingHPOs HP:0001987 (Hyperammonemia)

HPOsFreeText severe hyperammonemia at 48h of life

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(<2[normal 16-40μmol/l]), glutamine(1600[normal 530–913μmol/l]) and ammonia(3400[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.2440C>T (p.Arg814Trp), 2. NM_001875.4:c.3953T>A (p.Leu1318Ter) compound heterozygous

ClinVar n/a

CAID 1. CA2086638, 2. CA350439297

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 21120950

CasePt9 male, 5do death, Italian

CasePresentingHPOs HP:0001987 (Hyperammonemia)

HPOsFreeText Hyperammonemia

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing: ammonia(2750[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.2429A>G (p.Gln810Arg), 2. NM_001875.4:c.3953T>A (p.Leu1318Ter) compound heterozygous

ClinVar n/a

CAID 1. CA350440293, 2. CA350439297

gnomAD n/a

VariantEvidence n/a

CaseAddInfo n/a

CasePMIDs 12955727

CasePt5 male, 15mo death, Italian

CasePresentingHPOs HP:0001987, HP:0001254, HP:0001252, HP:0003572, HP:0003217 (Hyperammonemia, Lethargy, Hypotonia, Low plasma citrulline, High plasma glutamine)

HPOsFreeText neonatal severe hyperammonemia, mildly hypotonic, lethargy, low plasma citrulline, elevated glutamine

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(6[normal 16-40μmol/l]), glutamine(1500[normal 530–913μmol/l]) and ammonia(1214[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.1440_1441del (p.Thr481CysfsTer?), 2. NM_001122634.3:c.3004C>T (p.Arg1002Trp) compound heterozygous

ClinVar n/a

CAID 1. CA2086366, 2. CA64748170

gnomAD 1. 0.00001802(European (Non-Finnish), 0.000008153(Total), 2. n/a

VariantEvidence n/a

CaseAddInfo Older brother who died with post-mortem suspicion of CPSD or NAGS deficiency.

CasePMIDs 21120950

Family#PresentingHPOs HP:0001987 (Hyperammonemia)

HPOFreeText: Severe hyperammonemia

FamilyNotHPOs n/a

CountryOrigin n/a

Ethnicity Italian

Race n/a

Family#PreviousTesting Elevated plasma ammonia in both siblings (3454 in Pt7 and 1858 in Pt8[normal<75 μg/dl]).

Family#Method1 PCR

Family#Method2 n/a

Family#GenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Affected 2

Unaffected n/a

Segregations n/a

PublishedLOD n/a

eLOD n/a

AddSegregationInfo n/a

ProbandLabel Pt7, Female, 5mo death

CasePresentingHPOs HP:0002283, HP:0100806, HP:0003572, HP:0003217 (Diffuse brain atrophy, Sepsis, Low plasma citrulline, High plasma glutamine)

CaseHPOsFreeText Severe hyperammonemia(2do), Severe diffuse brain atrophy on MRI(1mo), sepsis(5mo)

CasePreviousTesting Low plasma citruline(0[normal 16-40μmol/l]) and elevated glutamine(2488[normal 530–913 μmol/l])

Variant 1. NM_001875.4:c.1263+5G>C, 2. NM_001875.4:c.2429A>G (p.Gln810Arg)

ClinVar n/a

CAID 1. To register, 2. CA350440293

gnomAD n/a

VariantEvidence c.1263+5G>C causes a splice defect (Table 2)

FamilyAddInfo Brother, Pt8, died with similar clinical features and was diagnosed with CPS1D post-mortem.

FamilyPMIDs 12955727, 12655559

CasePt1 female, 3yo diagnosis, Italian

CasePresentingHPOs HP:0001508, HP:0002014, HP:0000505, HP:0002167, HP:0002013, HP:0001252, HP:0002321, HP:0001987, HP:0003217, HP:0002910, HP:0012747, HP:0100543, HP:0001256 (Failure to thrive, Diarrhea, Visual impairment, Speech impairment, Vomiting, Hypotonia, Vertigo, Hyperammonemia, Hyperglutaminemia, Elevated transaminases, Abnormal brain MRI signal intensity, Cognitive impairment, Mild ID)

HPOsFreeText normal psychomotor dev, failure to thrive and diarrhea(first years), visual/speech impairment, vomiting, hypotonia, vertigo(referred at 3y,2mo), , hyperammonemia, high glutamine, elevated transaminases, normal orotic levels, hyperintense signal in cortical-subcortical frontal region on brain MRI, cognitive impairment:IQ 53(3yo) mild ID(21yo)

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing plasma citrulline(17.3[normal 16-40μmol/l]), glutamine(1244[normal 530–913μmol/l]) and ammonia(300[normal< 75 μg/dl]), elevated transaminases 350 UI/L, normal orotic levels, CPS1 residual enzyme activity "low" in liver biopsy.

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4(CPS1):c.3047A>G (p.Asn1016Ser), 2. NM_001875.4:c.3500C>G (p.Thr1167Arg) compound het

ClinVar 1. 551211

CAID 2. CA350437190

gnomAD 1. 0.00006534(African), 0.000008123(Total) 2. n/a

VariantEvidence enzyme assay showing low CPS1 activity mentioned

CaseAddInfo n/a

CasePMIDs 21120950

CasePt3 male, 4yo death, Italian

CasePresentingHPOs HP:0001987 (Hyperammonemia)

HPOsFreeText Severe hyperammonemia at 48h of life

CaseNotHPOs n/a

CasePreviousTesting Metabolic testing: ammonia(348[normal< 75 μg/dl])

CaseMethod1 PCR

CaseMethod2 n/a

CaseGenotypingMethod PCR using primers 80 nucleotides from the splice sites flanking the 38 exons of CPS1. Tested both patients and parents. (found in 12955727, Funghini et al. (2003))

Variant 1. NM_001875.4:c.1022T>C(p.Leu341Ser), 2. NM_001875.4:c.3784C>T(p.Arg1262Ter ) compound heterozygous

ClinVar n/a

CAID 1. CA350430554, 2. CA350438463

gnomAD 1. n/a, 2. 0.00004485(European (Finnish)), 0.000004062(Total)

VariantEvidence n/a

CaseAddInfo similarly affected brother died without diagnosis

CasePMIDs n/a

PMID: 29801986

Gene: CPS1

Disease: Carbamoyl phosphate dehydrogenase deficiency

MONDO:0009376

InheritancePattern: AR

Gene: CPS1

MONDO:0009376

carbamoyl phosphate synthetase I deficiency disease

Inheritance: Autosomal recessive

PMID 21120950