FamilyGL: N/A

FamilyPresentingHPOs: HP:0012237 (Urocanic aciduria)

HPOsFreeText: N/A

FamilyNotHPOs: HP:0001507, HP:0100543, HP:0010904 (Growth abnormality, Cognitive impairment, Abnormal circulating histidine concentration)

NotHPOsFreeText: N/A

FamilyGenotypingMethod: Genomic DNA was obtained via peripheral blood from the siblings and both parents. PCR and direct sequencing in both forward and reverse directions was used to amplify and sequence the 21 coding exons of UROC1.

FamilyPreviousTesting: Plasma samples from both subjects demonstrated significant elevations in cis-urocanate, trans-urocanate and imidazole propionate; Z-scores for compounds in alternative histidine degradation pathways were found to be within normal limits, including 1-methylhisitidine, imidazole lactate, and 1-methylhistamine; Table 1 shows detailed metabolite levels; Family history was negative for metabolic disorders or any other familial diseases

FamilyAddInfo: Family appears to be asymptomatic, Siblings are confirmed compound heterozygous via parental sequencing (father het for Variant 2, mother het for Variant 1)

Variant1: NM_144639.3:c.356C>G (p.Pro119Arg)

CAID: CA2591587, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2591587

gnomAD: 0.0001596, https://gnomad.broadinstitute.org/variant/3-126227314-G-C

Variant2: NM_144639.3:c.907G>C (p.Ala303Pro)

CAID: CA2591263, http://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA2591263

gnomAD: 0.00009300, https://gnomad.broadinstitute.org/variant/3-126220119-C-G

Affected: 2

Unaffected: 3

AddSegregationInfo: Not enough affected

CaseES: Female, 1 yr onset

CasePresentingHPOs: HP:0002312, HP:0002131, HP:0002719, HP:0002078, HP:0002066, HP:0100560, HP:0002345, HP:0008376, HP:0000666, HP:0001348, HP:0002342, HP:0410217, HP:0012237 (Clumsiness, Episodic ataxia, Recurrent infections, Truncal ataxia, Gait ataxia, Upper limb asymmetry, Action tremor, Dysarthic speech, Horizontal nystagmus, Brisk reflexes, Moderate intellectual disability, Reduced blood 5-methyltetrahydrofolate level, Urocanic aciduria)

HPOsFreeText: Urocanis acid levels 158-202 mmol/mol creatinine (reference <10)

CaseNotHPOs: HP:0000496, HP:0001324, HP:0002160, HP:0001903 (Abnormal ocular movements, Muscle weakness, Hyperhomocystinemia, Anemia)

NotHPOsFreeText: N/A

CaseAddInfo: Parents are healthy and nonconsanguineous, Steady improvement after mid-life, Proband is confirmed compound heterozygous by parental confirmation (father heterozygous for Variant 2)

CasePreviousTesting: Cranial MRI and neurophysiological studies, including electroencephalography, electroretinography, visual and brainstem evoked potentials, electromyography, nerve conduction velocities, fundus oculi and cardiological examinations, gave normal results; Cognitive evaluation rated her IQ at 54; Routine laboratory analyses including serum amino transferases, creatinine, urea and other parameters were normal; Screening for inborn errors of metabolism, including plasma and urine amino acids (no histidine accumulation), blood lactate, sialotransferrin isoelectricfocusing, creatine deficiency syndromes, purine and pyrimidine defects, and organic acidurias, gave normal results; Hypothyroidism and coeliac disease were also excluded; Biochemical and/or genetic screening for early onset forms of inherited ataxia gave normal results; Deficiencies in 5-methyltetrahydrofolate, neopterin and biopterin deficiencies were seen, together with an evident reduction in homovanillic acid (HVA) and the HVA:5-hydroxyindolacetic acid ratio; Other parameters determined in cerebrospinal fluid (CSF), such as glucose, proteins, cells and amino acids were normal.

CaseGenotypingMethod: Genomic DNA was obtained from peripheral white blood cells from the proband and her father. Mutation analysis of UROC1 was performed via direct sequencing and PCR amplification of the 20 exons and flanking exon-intronic sequences. In-silico analysis and modeling was performed on the variants.

Variant1: NM_144639.3(UROC1):c.209T>C (p.Leu70Pro)

ClinVar: 408 https://www.ncbi.nlm.nih.gov/clinvar/variation/408/

gnomAD: 0.00005647, https://gnomad.broadinstitute.org/variant/3-126229555-A-G

Variant2: NM_144639.3(UROC1):c.1348C>T (p.Arg450Cys)

ClinVar: 407, https://www.ncbi.nlm.nih.gov/clinvar/variation/407/

gnomAD: 0.00008012, https://gnomad.broadinstitute.org/variant/3-126216984-G-A