Case#: Patient 5, Japanese, 8 years old (report) CaseHPOs: Hyperornithinemia

CaseHPOsFreeText: (From Hayasaka et al. 1981; PMID 7260021, Patient 2). First noted visual problems at age 5 years, glasses prescribed for myopia. Evaluation for night blindness at age 8. Best corrected visual acuity was RE 04 with correction of myopia (-8 D), LE 04 with correction of myopia (-10 D). Typical chorioretinal atrophy with scallop margins at the peripheral fundus and an abnormal reflex in the macular area. Concentric constriction of visual fields. Dark adaptation curve was monophasic. ERG was subnormal, and the electro-oculogram was flat. The ciliary processes were normal by cycloscopy. Not responsive to Vitamin B6.

CaseNotHPOsFreeText: Normal lens

CasePreviousTesting: Serum ornithine 12.95 mg/dl (normal 0-36-1-56). OAT activity was not detectable in cell extracts from skin fibroblasts. CaseAddInfo: No consanguinity reported CaseMethod1: PCR

CaseMethod2: Sequence analysis

CaseGenotypingMethod: DGGE and sequence analysis of genomic DNA was carried out to identify the variant on the other allele. Variant: NM_000274.3(OAT):c.1276C>T (p.Arg426Ter)

ClinVar: 177

gnomAD: Maximum population minor allele frequency = 0.00002893 (Latino); no homozygotes in any population.

Case#: Patient 2; English/Dutch/German/French

CaseHPOs: Clinical details in Weleber et al, 1982, “Gyrate atrophy of the choroid and retina… Birth defects: Original Article Series 18 (6) 219-230. Article has been requested.

CaseHPOsFreeText: Not responsive to Vitamin B6.

CaseNotHPOs:

CasePreviousTesting: OAT activity was nondetectable in the patient’s fibroblasts. Northern analysis detected no OAT mRNA. Western blot analysis of OAT protein in the patient's fibroblasts demonstrated an essentially negligible amount of OAT.

CaseMethod1: PCR

CaseMethod2: Sequence analysis

CaseGenotypingMethod: Truncated 5.0-kbp EcoRI OAT gene fragment in addition to the normal 5.8-kbp fragment on Southern blot analysis (Inana et al., 1988), suggesting heterozygosity for a deletion. Cloning and sequencing of the truncated fragment revealed a deletion of 1,072 base pairs. DGGE and sequence analysis of genomic DNA was carried out to identify the variant on the other allele.

Variant: Variant 1: A 1,072-bp deletion starting in intron 5, 172 bp upstream of exon 6, and ending in intron 6, 772 bp downstream of exon 6 Variant 2: NM_000274.3(OAT):c.627T>A (p.Tyr209Ter)

ClinVar: Variant 1: 174; Variant 2: 175

gnomAD: Variant 1: Not listed (but large deletion may not be picked up) Variant 2: Maximum population minor allele frequency = 0.00004645 (European non-Finnish); no homozygotes in any population.

Case#: GA8, England, 15 years (onset), gender unknown.

CaseHPOs: HP:0000662, HP:0012026 (night blindness, (hyperornithinemia)

CaseHPOsFreeText: Presented with visual disturbances. Vitamin B6 responsive.

CaseNotHPOs: Neonatal encephalopathy

CasePreviousTesting: No previous DNA testing noted. Plasma ornithine at diagnosis 728 umol/L (normal <100)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Sequence analysis of the OAT gene from fibroblast or lymphocyte cDNA and genomic DNA. Variant: NM_000274.3(OAT):c.952G>A (p.Glu318Lys)

ClinVar: 56138

gnomAD: The maximum population minor allele frequency in gnomAD is 0.00002328 (European non-Finnish); no homozygotes in any population. VariantEvidence: When the variant was expressed in yeast, OAT enzymatic activity was <10% normal. This variant did not significantly affect protein levels but displayed a marked reduction of the hexamer (the active form) and an accumulation of the monomeric form.

Case#: GA5, Southern Italy, 40 years (onset), gender unknown

CaseHPOs: HP:0000662, HP:0012026 (night blindness, (hyperornithinemia)

CaseHPOsFreeText: Presented with visual disturbances at age 40 years. Plasma ornithine levels could be normalized by diet alone. Not responsive to Vitamin B6 treatment.

CaseNotHPOs: Neonatal encephalopathy

CasePreviousTesting: No previous DNA testing noted. Plasma ornithine at diagnosis 805 umol/L (normal <100)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Sequence analysis of the OAT gene from fibroblast or lymphocyte cDNA and genomic DNA. Variant: NM_000274.3(OAT):c.1307T>A (p.Ile436Asn)

ClinVar: 56115

gnomAD: The maximum population minor allele frequency in gnomAD = 0.00002662 (European non-Finnish); no homozygotes in any population.

VariantEvidence: The variant was expressed in S. cerevisae with a deletion of CargB, the year ortholog of OAT, that cannot grow in media with ornithine as the sole nitrogen source. Whereas expression of wild type OAT allows yeast to grow in media with ornithine as the sole nitrogen source, no growth was observed when the variant was expressed. OAT enzymatic activity was measured and was <10% normal, and OAT protein was barely detectable on Western blot.

Case#: GA3, Turkey, 5 years (onset), gender unknown

CaseHPOs: HP:0012026 (hyperornithinemia)

CaseHPOsFreeText: Presented with visual disturbances at 5 years of age. No further details.

CaseNotHPOs: Neonatal encephalopathy

CasePreviousTesting: No previous DNA testing noted. Plasma ornithine at diagnosis 650umol/L (normal <100)

CaseMethod1: PCR

CaseMethod2: Sequencing

CaseGenotypingMethod: Sequence analysis of the OAT gene from fibroblast or lymphocyte cDNA and genomic DNA. Variant: NM_000274.3(OAT):c.991C>T (p.Arg331Ter) (homozygous)

ClinVar: 56141

gnomAD: The maximum population minor allele frequency in gnomAD is 0.0001446 (Latino); no homozygotes in any population.

Case#: Pedigree 6 proband, Finland

CaseHPOs: HP:0012026 (hyperornithinemia)

CaseHPOsText: Patient noted to be "of historical interest" because he was the first patient in whom hyperornithinemia was recognized in gyrate atrophy (PMID 4122112). At age 8, choroidal degeneration ultimately diagnosed as gyrate atrophy, abnormal ERG; plasma ornithine concentration 10 times normal.

CaseGenotypingMethod: Variant identified by sequencing of genomic clones of OAT; sequencing of the remainder of the coding region and exon/intron boundaries was normal.

Variant: NM_000274.3(OAT):c.539G>C (p.Arg180Thr) (homozygous)

ClinVarID: 153

gnomAD: Maximum population minor allele frequency = 0.0007166 (Finnish); no homozygotes

VariantEvidence: When expressed in CHO-K1 cells, the variant results in no detectable OAT activity. Another Finnish patient (out of a group of 16) was also found to be homozygous for this variant.

Family#: GA-07, Lebanese Maronite

FamilyHPOs: HP:0012026

FamilyHPOText: “Clinical presentation typical of gyrate atrophy”; no further details.

FamilyGenotypingMethod: RNAse A protection assay using 2 probes to cover the entire OAT cDNA, narrowed the site of the variant to the 5’ end of the gene. DNA sequence analysis revealed c.3G>A (p.Met1?). Parents are confirmed heterozygous, based on RFLP analysis.

FamilyPreviousTesting: Elevated plasma ornithine; Fibroblast OAT activity was undetectable

Variant: NM_000274.3(OAT):c.3G>A (p.Met1?)

ClinVar: 146

gnomAD: Not in gnomAD

Proband: GA-07, Case 7, female, Lebanese, 32 (at report)

CasePreviousTesting: Plasma ornithine, on normal diet: 771uM/l (normal 75+/-25). Fibroblast OAT activity was undetectable (ornithine value from Kaiser-Kupfer, M. I., and D. Valle. 1986. Progress in Retinal Research. p179-206)

CaseAddInfo: Parents are confirmed heterozygotes.

Sibling: GA-07, Case 16, male, Lebanese, 33 (at report)

SiblingPreviousTesting: Plasma ornithine, on normal diet: 800uM/l (normal 75+/-25). Fibroblast OAT activity was undetectable (ornithine value from Kaiser-Kupfer, M. I., and D. Valle. 1986. Progress in Retinal Research. p179-206)

Points: 1 point

Family#: JU#0213, Japanese

FamilyHPOs: HP:0012026

FamilyGenotypingMethod: PCR, sequencing of the coding exons (3-11) of the OAT gene from genomic DNA

Variant: 1) c.504_505delAA (p.K169DfsX10) (mother) 2) c.1276C>T (p.R426X) (last exon) (father)

ClinVar: 1) NA; 2) 177

CAID: 1) CA913187453

gnomAD: The maximum population minor allele frequency for c.1276C>T (p.R426X) is 0.00002893 (Latino); no homozygotes in any population. c.504_505delAA is not in gnomAD.

Proband: JU#0213:II-1