FANCL – Fanconi anemia

FANCL encodes a PHD/RING-finger E3 ubiquitin ligase that catalyzes monoubiquitination of the FANCD2–FANCI dimer, a central step in the Fanconi anemia (FA) DNA interstrand crosslink repair pathway. Biallelic loss-of-function variants in FANCL define the FA-L complementation group, an autosomal recessive subtype of Fanconi anemia. FA patients typically present in early childhood with progressive bone marrow failure, congenital malformations, and increased cancer risk.

Initial genetic evidence comes from the second reported FA-L case, in which compound heterozygous FANCL frameshift and splice-site variants were identified and functionally corroborated via FA complementation assay (PMID:19405097). A Chinese girl with FA-L was shown to harbor a novel homozygous frameshift insertion c.822_823insCTTTCAGG (p.Asp275LeufsTer13) and developed bone marrow failure progressing to AML at age nine (PMID:28419882). A recurrent synonymous founder variant c.1092G>A, inducing exon skipping and deletion of p.Trp341_Lys364, accounts for 13 South Asian FA cases, representing ~19% of Indian FA-L alleles (PMID:31513304). Altogether, these reports comprise at least 17 unrelated probands across six families with homozygous or compound heterozygous FANCL variants.

The variant spectrum in FA-L is dominated by truncating (frameshift, nonsense) and splice-site mutations. No clearly pathogenic missense variants have been reported to date. The prototypical insertion variant c.822_823insCTTTCAGG (p.Asp275LeufsTer13) illustrates the deleterious effect of frameshifts in FANCL exons (PMID:28419882).

Functional studies demonstrate that FANCL deficiency impairs the core complex: Drosophila FANCL knockdown results in hypersensitivity to cross-linking agents and loss of FANCD2 monoubiquitination, recapitulating human cellular defects (PMID:16860002). Ectopic expression of wild-type FANCL in patient cells restores chromosome stability and complementation activity, underscoring a loss-of-function mechanism (PMID:25754594).

No studies have refuted the association of biallelic FANCL variants with FA-L; phenotype and cytogenetic breakage assays are concordant across cohorts. The absence of conflicting evidence supports a robust gene–disease link.

Integration of genetic and experimental data establishes FANCL as a definitive FA gene in the FA-L group. Molecular screening panels should include truncating and splice mutations, with particular attention to the c.1092G>A founder allele in South Asian populations. Key Take-home: Biallelic FANCL loss-of-function variants conclusively cause FA-L and should be incorporated into diagnostic algorithms, enhancing early detection and management.

References

• Human mutation • 2009 • Identification and characterization of mutations in FANCL gene: a second case of Fanconi anemia belonging to FA-L complementation group. PMID:19405097
• European journal of medical genetics • 2017 • Novel homozygous FANCL mutation and somatic heterozygous SETBP1 mutation in a Chinese girl with Fanconi Anemia. PMID:28419882
• Human mutation • 2020 • A founder variant in the South Asian population leads to a high prevalence of FANCL Fanconi anemia cases in India. PMID:31513304
• DNA repair • 2006 • Drosophila homologs of FANCD2 and FANCL function in DNA repair. PMID:16860002
• Human mutation • 2015 • Loss-of-Function FANCL Mutations Associate with Severe Fanconi Anemia Overlapping the VACTERL Association. PMID:25754594

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