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Fanconi anemia (FA) is an autosomal recessive genome instability syndrome characterized by progressive bone marrow failure, congenital anomalies, and cancer predisposition, caused by biallelic mutations in any of 22 FANC genes. PALB2 (FANCN) encodes a BRCA2-binding protein that localizes BRCA2 to DNA damage sites and is essential for interstrand crosslink repair via homologous recombination. Loss of PALB2 function disrupts the FA/BRCA pathway, leading to chromosomal breakage and FA phenotype.
Genetic studies established PALB2 as FA gene FANCN when biallelic truncating mutations were identified in seven unrelated families (≥14 affected individuals) with early-onset FA, designated FA-N ([PMID:17200671]). All probands harbored two loss-of-function alleles, including recurrent nonsense and frameshift variants. One representative pathogenic allele is c.3491G>A (p.Trp1164Ter) found in multiple pedigrees.
Segregation analysis in these families showed complete cosegregation of biallelic PALB2 mutations with FA phenotype in siblings and cousins, confirming autosomal recessive inheritance (affected_relatives = 14) ([PMID:17200671]). The variant spectrum in FA-N comprises predominantly truncating and splice‐site mutations across PALB2’s WD40 domain, with no apparent hypomorphic alleles causing FA.
Functional assays in patient‐derived cells and murine models demonstrate that PALB2 deficiency abolishes FANCD2 monoubiquitination, impairs RAD51 foci formation, and confers hypersensitivity to DNA crosslinkers, recapitulating FA cellular phenotypes. Palb2 knockout in mice is embryonic lethal, while conditional deletion in fibroblasts leads to chromosomal instability and defective homologous recombination.
No conflicting evidence disputes PALB2’s role in FA-N. Heterozygous carriers remain asymptomatic for FA but are at elevated cancer risk, consistent with recessive inheritance. Together, genetic and biochemical data conclusively define biallelic PALB2 deficiency as causal for FA-N.
Key take-home: Biallelic loss-of-function mutations in PALB2 underlie Fanconi anemia subtype FA-N through failure of the FA/BRCA DNA repair pathway, informing diagnostic genetic testing, counseling, and potential targeted therapies.
Gene–Disease AssociationDefinitiveBiallelic PALB2 mutations identified in 7 unrelated FA-N families with consistent segregation and functional concordance Genetic EvidenceStrongSeven families, ≥14 affected individuals with biallelic truncating variants, AR inheritance, variant spectrum predominantly loss-of-function ([PMID:17200671]) Functional EvidenceModerateCellular assays demonstrate impaired DNA repair and hypersensitivity to crosslinking agents in PALB2-deficient cells |