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FOXRED1 – Leigh syndrome

FOXRED1 has been implicated in Leigh syndrome through identification of biallelic variants in multiple unrelated families. Initial discovery in a consanguineous pedigree employed homozygosity mapping to uncover a homozygous c.1054C>T (p.Arg352Trp) variant, with lentiviral-mediated transgene expression restoring complex I activity in patient fibroblasts (PMID:20858599).

Autosomal recessive inheritance is supported by at least 10 unrelated probands harboring two pathogenic alleles, including consanguineous and outbred cohorts (PMID:33613441; PMID:38283147). Segregation analyses across pedigrees consistently align with recessive transmission.

The variant spectrum encompasses frameshift (e.g., c.862_871dup (p.Ala291fs)), nonsense (c.90G>A (p.Trp30Ter)), splice-site (c.733+1G>A), and missense (c.920G>A (p.Gly307Glu)) alterations. Notably, recurrent variants c.1054C>T (p.Arg352Trp) and c.612_615dupAGTG (p.Ala206SerfsTer15) have been observed in multiple populations (PMID:33613441; PMID:31065540).

Clinically, affected individuals present with early-onset encephalopathy characterized by global developmental delay (HP:0001263), epilepsy (HP:0001250), lactic acidosis (HP:0003128), and cerebral atrophy (HP:0002058). Additional features include pulmonary hypertension and periventricular cysts in isolated cases.

Functional assays demonstrate decreased complex I holoenzyme levels and enzymatic activity in patient-derived fibroblasts, which are rescued by wild-type FOXRED1 complementation (PMID:20858599; PMID:31434271). Biochemical investigations implicate loss of FAD-dependent oxidoreductase activity in defective complex I assembly (PMID:20818383).

No conflicting evidence has been reported to dispute this association. Collectively, the genetic and experimental data support a Strong clinical validity for FOXRED1 in Leigh syndrome. Key take-home: inclusion of FOXRED1 in diagnostic panels for mitochondrial complex I deficiencies enhances molecular diagnosis and patient management.

References

  • Nature genetics • 2010 • High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. PMID:20818383
  • Human molecular genetics • 2010 • FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. PMID:20858599
  • Journal of clinical medicine • 2019 • Identification and Characterization of New Variants in FOXRED1 Gene Expands the Clinical Spectrum Associated with Mitochondrial Complex I Deficiency. PMID:31434271
  • Frontiers in neurology • 2021 • Clinical and Genetic Characteristics of Mitochondrial Encephalopathy Due to FOXRED1 Mutations: Two Chinese Case Reports and a Review of the Literature. PMID:33613441
  • Frontiers in genetics • 2023 • Expanding the genetic spectrum of mitochondrial diseases in Tunisia: novel variants revealed by whole-exome sequencing. PMID:38283147

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

At least 10 unrelated probands with biallelic FOXRED1 variants in autosomal recessive families (PMID:33613441; PMID:38283147), multi-study reports including consanguineous pedigree and diverse populations, and cross-cohort consistency.

Genetic Evidence

Strong

Ten distinct pathogenic variants (multiple frameshift, nonsense, splice-site, and missense) identified in unrelated individuals fulfilling autosomal recessive inheritance and reaching the ClinGen genetic evidence cap.

Functional Evidence

Moderate

Cellular complementation in patient fibroblasts (PMID:20858599; PMID:31434271) and FAD-dependent oxidoreductase assays confirm defective complex I assembly and rescue by wild-type FOXRED1.