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Glutaric acidemia type 3 (GA3) is a rare autosomal recessive organic aciduria characterized by impaired conversion of glutarate to glutaryl‐CoA due to succinate‐hydroxymethylglutarate coenzyme A‐transferase deficiency. The SUGCT gene (HGNC:16001) encodes this mitochondrial enzyme and localizes to chromosome 7p14. GA3 displays inconsistent expressivity, with many individuals asymptomatic despite markedly elevated urinary glutarate. Autosomal recessive inheritance was established through homozygosity mapping and sequencing ((PMID:18926513)). Biochemical profiling uniformly demonstrates an elevated urine glutarate to derivative ratio. The lack of distinctive clinical features historically limited GA3 recognition.
Two reports describe homozygous contiguous deletions spanning SUGCT and MPLKIP in an 8-year-old Peruvian girl ((PMID:29421601)) and an infant from a second cohort ((PMID:37064336)). These 125 kb and microdeletions on 7p14 eliminated SUGCT coding regions, confirming the critical role of null alleles in GA3. However, overlapping MPLKIP deletion causing trichothiodystrophy type 4 complicated phenotype interpretation. These cases underscore the importance of copy number analysis for patients with unexplained organic acidurias.
In Old Order Amish screening, three individuals with abnormal glutarate excretion but lacking the GA1-related GCDH mutation shared a 4.7 Mb homozygous region on chromosome 7 encompassing C7orf10 (SUGCT). Sequencing revealed a recurrent variant c.895C>T (p.Arg299Trp) in all three ((PMID:18926513)). Subsequent analysis of three non-Amish probands uncovered truncating alleles c.322C>T (p.Arg108Ter) and c.424C>T (p.Arg142Ter), establishing biallelic pathogenicity.
Three unrelated Canadian patients were characterized, two symptomatic and one identified via newborn screening, all harboring homozygous missense variants c.985C>T (p.Arg329Trp) or c.625G>A (p.Gly209Ser) in SUGCT ((PMID:28766179)). Clinical features included cyclic vomiting and gastrointestinal disturbances, with significant improvement following antibiotic therapy in one case.
Two siblings presented with isolated glutarate excretion and a novel homozygous missense variant c.964C>T (p.Leu322Phe) in SUGCT, alongside symmetrical periventricular and deep white matter MRI abnormalities ((PMID:32779420)).
In total, 11 probands across at least six unrelated families harbor six distinct pathogenic alleles—three truncating (p.Arg108Ter, p.Arg142Ter, p.Arg172Ter) and four missense (p.Arg299Trp, p.Arg329Trp, p.Gly209Ser, p.Leu322Phe)—in an autosomal recessive pattern ((PMID:18926513; PMID:28766179; PMID:32779420)). These variants consistently lead to glutarate accumulation, supporting a loss‐of‐function mechanism.
Functional assessment is limited to biochemical metabolite profiling, demonstrating elevated urinary glutarate consistent with impaired SUGCT activity. No cellular or animal models have been described, and rescue or expression studies are lacking.
This body of evidence supports a Strong ClinGen classification for the SUGCT–Glutaric acidemia Type 3 association, meeting criteria for replication and variant‐level confirmation. GA3 should be considered in the differential of organic acidurias, and testing strategies should include SUGCT sequencing and copy number analysis. Key take-home: Identifying biallelic SUGCT variants confirms GA3 diagnosis and enables targeted metabolic management.
Gene–Disease AssociationStrong11 probands (PMID:18926513; PMID:28766179; PMID:32779420), six unrelated families; AR inheritance; consistent biochemical phenotype Genetic EvidenceStrongBiallelic SUGCT variants in 11 probands across three cohorts; variant spectrum includes four missense and three truncating alleles Functional EvidenceLimitedSupported by biochemical assays demonstrating glutarate accumulation; no cellular or animal model data |