FANCX Gene Identified as Driver of Severe Fanconi Anemia

A newly identified genetic mutation in FANCX—previously known as FAAP100—has been confirmed as a causative factor in particularly severe forms of Fanconi anemia (FA), a rare inherited disorder that compromises bone marrow function and increases susceptibility to cancer. Published in The Journal of Clinical Investigation, this landmark study expands the catalog of FA-associated genes and deepens understanding of the DNA repair mechanisms underpinning the disease's pathology.

Fanconi anemia is characterized by an inability to repair DNA interstrand crosslinks, resulting in chromosomal instability, bone marrow failure, and congenital abnormalities. The discovery that FANCX mutations lead to loss of function in the FA core complex provides crucial insight into why some FA cases present with devastating severity. Specifically, FANCX encodes a structural subunit of the FA core complex that stabilizes and scaffolds the assembly of FANCB and FANCL. This trimeric unit is essential for the monoubiquitination of FANCD2 and FANCI—an early, pivotal step in DNA crosslink repair.

Disruption of this complex halts the FA pathway’s ability to initiate repair, leading to cellular hypersensitivity to DNA damage. The researchers showed that biallelic mutations in FANCX abolish this function entirely, correlating with fatal outcomes including miscarriages and neonatal death. In one case, a couple with multiple unexplained pregnancy losses gave birth to an infant with severe congenital anomalies who died shortly after birth. Whole-exome sequencing revealed pathogenic variants in both FANCX alleles, confirming its causative role (Harrison et al., 2025).

The findings were corroborated by a separate genetic analysis conducted at The Rockefeller University, which further demonstrated that FANCX mutations result in near-total loss of DNA repair capacity in cell models. This functional impairment explains the pronounced clinical manifestations, and highlights why FANCX-related FA may remain underdiagnosed in the absence of whole-genome or targeted gene panel testing.

With FANCX now recognized as the 23rd gene implicated in FA, the discovery holds significant implications for clinical practice. As emphasized by the Fanconi Anemia Research Fund, incorporating FANCX into comprehensive diagnostic gene panels will enable earlier detection of at-risk individuals. This could facilitate timely interventions such as hematopoietic stem cell transplantation and surveillance protocols for solid tumors and leukemia, to which FA patients are highly predisposed.

Beyond diagnostics, the discovery opens avenues for novel therapeutic strategies. By targeting the structural dynamics of the FA core complex, researchers may be able to develop gene therapies or molecular stabilizers that restore partial function in mutated FANCX. While such treatments remain theoretical, the elucidation of FANCX's role provides a promising foundation for precision medicine approaches in FA.

The severity of FANCX-associated FA also renews focus on reproductive counseling and preimplantation genetic testing. Families with a history of early miscarriage or congenital anomalies should be offered expanded screening options to identify rare but consequential mutations like those in FANCX, particularly given the rapid pace of gene discovery in rare disease research.