RECQL4 – Osteosarcoma

Germline biallelic variants in RECQL4 underlie Rothmund-Thomson syndrome, an autosomal recessive disorder with predisposition to Osteosarcoma (PMID:12734318). Patients present with poikiloderma, short stature, and skeletal dysplasia, with osteosarcoma arising in adolescence and young adulthood.

In an international cohort of 33 RTS patients, 23 carried at least one truncating RECQL4 mutation and all 11 osteosarcoma cases were mutation-positive. The incidence of osteosarcoma was 0.05 per year in truncation-positive patients versus 0 in truncation-negative subjects (P = .037) (PMID:12734318). This AR pattern highlights the necessity of biallelic loss-of-function for tumor predisposition.

The variant spectrum is dominated by frameshift and nonsense changes across RECQL4 exons, exemplified by c.2782G>T (p.Glu928Ter). These truncations abolish helicase activity, leading to replication stress and genomic instability in osteoblast progenitors.

Functional studies support a loss-of-function mechanism. Exon-13–deleted Recql4-deficient mice exhibit severe growth retardation, skin abnormalities, and embryonic fibroblast proliferation defects mirroring human RTS phenotypes (PMID:12915449).

At the molecular level, RECQL4 participates in non-homologous end joining. RECQL4 knockdown cells show reduced in vitro end-joining activity, increased γ-irradiation sensitivity, and impaired recruitment of the Ku70/Ku80 complex to DNA double-strand breaks, confirming a defect in DSB repair (PMID:24942867).

Together, genetic and experimental evidence establish a strong gene–disease association between biallelic RECQL4 truncating variants and osteosarcoma risk in RTS. Molecular diagnosis of RECQL4 LoF variants enables identification of high-risk individuals and informs surveillance strategies. Key take-home: Germline truncating RECQL4 variants are a significant predictive biomarker for osteosarcoma in Rothmund-Thomson syndrome.

References

• Journal of the National Cancer Institute • 2003 • Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. PMID:12734318
• Human Molecular Genetics • 2003 • Growth retardation and skin abnormalities of the Recql4-deficient mouse. PMID:12915449
• Carcinogenesis • 2014 • RECQ helicase RECQL4 participates in non-homologous end joining and interacts with the Ku complex. PMID:24942867

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