ERCC6L2 – Pancytopenia

ERCC6L2 has emerged as a critical gene associated with pancytopenia, a hematological disorder characterized by reduced counts across multiple blood cell lineages. Multiple independent studies have established that biallelic loss‐of‐function mutations in ERCC6L2 predispose affected individuals to bone marrow failure syndromes and, in some cases, to progression toward myeloid malignancies (PMID:36952636). The clinical presentations are often subtle, with patients showing mild cytopenias despite significant bone marrow hypoplasia.

Clinical case‐report data underscore the autosomal recessive inheritance of this condition. In one pivotal study, a cohort of 52 subjects from 35 families with pancytopenia harbored biallelic truncating mutations in ERCC6L2, with further segregation analyses revealing approximately 19 additional affected relatives consistently manifesting similar phenotypes (PMID:36952636; PMID:29146883). These findings strongly support a deleterious role for ERCC6L2 mutations in altering hematopoietic homeostasis.

At the genetic level, case series and multi-patient investigations have identified a broad spectrum of pathogenic variants. Notably, a recurrent founder event, represented by the variant c.1424delT (p.Ile475ThrfsTer), has been reported in Finnish patients and corroborates the causative link between ERCC6L2 and pancytopenia (PMID:36952636). The genetic evidence is reinforced by the identification of various other truncating alterations in unrelated probands, all of which converge on a loss-of-function mechanism.

Functional analyses add further weight to the association. Experimental models using patient-derived cells and knockdown systems demonstrate that loss of ERCC6L2 impairs DNA repair pathways, compromises mitochondrial function, and disrupts RNA polymerase II-mediated transcription recovery. These biochemical defects are consistent with the clinical observations of bone marrow hypoplasia and altered hematopoiesis, thereby providing concordant functional validation of the gene-disease relationship (PMID:24507776; PMID:32846126).

Moreover, the integration of genetic and functional data highlights a clear pathogenic mechanism in which ERCC6L2 deficiency causes defective DNA repair and transcription termination. Such molecular derangements lead to genomic instability and aberrant marrow cellularity, which underlie the clinical picture of pancytopenia. Notably, additional studies indicate that the impact of ERCC6L2 dysfunction may extend beyond hematopoiesis, suggesting broader implications for patient management and monitoring.

Taken together, the robust genetic findings—including multiple independent probands, clear autosomal recessive segregation, and a recurrent founder mutation—coupled with compelling functional evidence, establish a strong causal relationship between ERCC6L2 and pancytopenia. This consolidated evidence base not only meets but exceeds current ClinGen scoring criteria, reinforcing the clinical utility of ERCC6L2 testing in diagnostic and therapeutic decision-making.

Key take‑home sentence: The integration of genetic and functional evidence confirms that ERCC6L2 is a bona fide driver of pancytopenia, underscoring its value as a diagnostic and prognostic biomarker in clinical hematology.

References

• Blood • 2023 • The clinical picture of ERCC6L2 disease: from bone marrow failure to acute leukemia. PMID:36952636
• Blood • 2018 • A landscape of germ line mutations in a cohort of inherited bone marrow failure patients. PMID:29146883
• American journal of human genetics • 2014 • ERCC6L2 mutations link a distinct bone‑marrow‑failure syndrome to DNA repair and mitochondrial function. PMID:24507776
• Cell reports • 2020 • Functional Radiogenetic Profiling Implicates ERCC6L2 in Non‑homologous End Joining. PMID:32846126
• Proceedings of the National Academy of Sciences of the United States of America • 2018 • Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants. PMID:29987015
• British journal of haematology • 2022 • Germline ERCC excision repair 6 like 2 (ERCC6L2) mutations lead to impaired erythropoiesis and reshaping of the bone marrow microenvironment. PMID:36156210

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