SLX4 – Fanconi Anemia

Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by chromosome instability, progressive bone marrow failure, congenital malformations, and cancer predisposition. SLX4 (FANCP) encodes a scaffold protein that coordinates structure-specific endonucleases for DNA interstrand crosslink repair. Biallelic SLX4 mutations define the FA-P subtype within the FA spectrum and underscore the critical role of SLX4 in genome maintenance. FA patients typically present in early childhood with hematologic abnormalities and a range of congenital anomalies, including short stature, hyperpigmentation, and genitourinary defects.

Genetic evidence for SLX4 involvement in FA includes biallelic truncating variants identified in three unrelated individuals across two families. Two patients were reported with compound SLX4 mutations, including a splice-site and a frameshift allele, in a foundational study establishing SLX4 as FANCP ([PMID:21240275]). A subsequent case report described a novel homozygous c.4921dupA>AC (p.Val1641GlyfsTer15) variant confirmed by Sanger sequencing in a third FA patient, with parental and fetal carrier testing supporting segregation ([PMID:39841989]).

Although extended pedigrees are limited, the c.4921dupA>AC (p.Val1641GlyfsTer15) variant segregated with disease in one nuclear family, confirming autosomal recessive inheritance with carrier status in obligate heterozygotes ([PMID:39841989]). No FA phenotype was observed in heterozygous carriers, consistent with the recessive mechanism.

The SLX4 variant spectrum in FA-P includes frameshift, splice-site, and large deletion alleles. At least three probands harbor loss-of-function mutations: c.514del (p.Leu172fs) and c.1163+2T>A were reported in the discovery cohort ([PMID:21240275]), and c.4921dupA>AC (p.Val1641GlyfsTer15) was described in the case report ([PMID:39841989]). No recurrent or founder alleles have been documented to date. Phenotypic features among SLX4-mutated cases align with classic FA manifestations.

Functional studies provide moderate corroboration: SLX4-deficient cells exhibit hypersensitivity to mitomycin C and diepoxybutane, and complementation with wild-type SLX4 restores DNA crosslink repair and chromosomal stability ([PMID:21240275]). Interactions with endonucleases such as XPF-ERCC1 and MUS81-EME1 are essential for SLX4 function, and disruption of these interactions impairs DNA repair pathways.

No conflicting evidence has been reported disputing SLX4’s role in FA. Monoallelic SLX4 variants have been investigated in breast cancer cohorts without clear pathogenic associations in the heterozygous state. To date, all pathogenic SLX4 alleles causing FA show autosomal recessive segregation.

Integration of genetic and functional data supports a Strong clinical validity for the SLX4–Fanconi anemia association. SLX4 mutation testing should be included in FA gene panels, facilitating definitive diagnosis, genetic counseling, and prenatal testing. Key take-home: Biallelic SLX4 loss-of-function variants cause FA-P and are critical biomarkers for diagnosis and management decisions.

References

• Nature genetics • 2011 • Mutations of the SLX4 gene in Fanconi anemia. PMID:21240275
• Genetic testing and molecular biomarkers • 2025 • Case Report: A Novel Homozygous Variant in the SLX4 Gene Causes Fanconi Anemia. PMID:39841989

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