FANCI – Fanconi anemia

Fanconi anemia (FA) group I is an autosomal recessive bone marrow failure syndrome caused by biallelic pathogenic variants in FANCI (HGNC:25568), characterized by chromosomal instability, pancytopenia, congenital malformations, and cancer predisposition ([PMID:17452773]).

Genetic evidence includes identification of FANCI mutations in at least 16 unrelated FA-I patients, with segregation observed in affected sib-pairs ([PMID:15139958]). This cohort comprises diverse variant classes—missense, nonsense, frameshift, and splice–site changes—across multiple families, fulfilling ClinGen criteria for a strong autosomal recessive gene–disease relationship ([PMID:26590883]).

The mutation spectrum features missense substitutions (e.g., homozygous c.668A>C (p.Lys223Thr)) ([PMID:39095039]), frameshifts, and splicing defects without evidence for recurrent or founder alleles. Segregation in multiple pedigrees confirms pathogenicity of these biallelic variants.

Functional assays demonstrate that FANCI is monoubiquitinated in an ATR-dependent manner and forms a heterodimeric ID complex with FANCD2, essential for DNA interstrand crosslink repair. Patient-derived truncating and C-terminal mutants (e.g., R1299X) abolish FANCD2 monoubiquitination, chromatin localization, and cellular resistance to crosslinkers, while wild-type FANCI expression rescues chromosomal breakage ([PMID:17412408]; [PMID:20971953]).

Additional studies reveal that the FANCI–FANCD2 complex has histone chaperone activity required for nucleosome assembly during repair, and zebrafish fanci knockouts exhibit growth retardation, sex reversal, and sterility, validating in vivo loss-of-function effects ([PMID:22828868]; [PMID:30540754]).

No conflicting evidence has emerged to dispute the causal role of FANCI in FA. Clinical testing for biallelic FANCI variants is recommended for early diagnosis, informs avoidance of DNA-damaging agents (e.g., cisplatin), and guides genetic counseling. Key take-home: Definitive evidence supports FANCI testing in FA diagnostics and management.

References

• Cellular Oncology • 2007 • Identification of the Fanconi anemia complementation group I gene, FANCI. PMID:17452773
• Blood • 2007 • FANCI is a second monoubiquitinated member of the Fanconi anemia pathway. PMID:17460694
• Cell • 2007 • Identification of the FANCI protein, a monoubiquitinated FANCD2 paralog required for DNA repair. PMID:17412408
• American Journal of Medical Genetics Part A • 2016 • Novel FANCI mutations in Fanconi anemia with VACTERL association. PMID:26590883
• Journal of Oncology Pharmacy Practice • 2024 • Cisplatin-induced bone marrow failure in an adult patient with Fanconi anemia. PMID:39095039
• Nucleic Acids Research • 2018 • Multiplexed CRISPR/Cas9-mediated knockout of 19 Fanconi anemia pathway genes in zebrafish revealed their roles in growth, sexual development and fertility. PMID:30540754

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