RECQL4 Mutations and Osteosarcoma: Comprehensive Genetics Evidence

By Nucleati Team
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Osteosarcoma, a malignant bone tumor primarily affecting children and adolescents, has long been associated with genetic factors. Recent studies have shed light on the involvement of RECQL4 mutations in osteosarcoma development. This blog article presents a comprehensive genetic evidence from multiple patients, exploring the link between RECQL4 gene mutations and the incidence and progression of osteosarcoma. The compilation of evidence and molecular insights aims to deepen our understanding of the role of RECQL4 in osteosarcoma pathogenesis. The tables are compiled with the help from Nucleati Germline Cancer Evidence Base.

Case Reports

Patient/Family Gene/Variation Clinical Characteristics HGVS(es) Citation
Six clinically diagnosed Rothmund-Thomson syndrome (RTS) patients RECQL4 gene mutations Growth deficiency, skin and bone defects, premature aging symptoms, cancer susceptibility NM_004260.4(RECQL4):c.2221G>A (p.Ala741Thr), NM_004260.4(RECQL4):c.2780T>G (p.Leu927Arg) PubMed
A patient with Baller-Gerold syndrome (BGS) and several clinical signs of Rothmund-Thomson syndrome (RTS) developed a midline NK/T-cell lymphoma RECQL4: c.[2492_2493delAT]+c.[2506_2518del13bp] The patient showed severe phenotypic abnormalities, with clinical signs of both BGS and RTS. She developed an extranodal NK/T-cell lymphoma, which is extremely rare in children of her age and is the first described case of BGS with the development of a cancer NM_004260.4(RECQL4):c.2492_2493del (p.His831fs) PubMed
Patient with compound heterozygosity for two novel RECQL4 mutations RECQL4:c.1919_1924delTCACAG,p.L640_A642delinsP and RECQL4:c.1704+1G>A Developed large cell anaplastic T cell lymphoma at age 9, diffuse large cell B lymphoma and osteosarcoma at age 14, and acute lymphatic leukemia at age 21 NM_004260.4(RECQL4):c.1919_1924del (p.Leu640_Ala642delinsPro), NM_004260.4(RECQL4):c.1704+1G>A, NM_004260.4(RECQL4):c.1704+2T>C PubMed
A man with features of RAPADILINO and RTS RECQL4 gene mutations: c.2767_2768delTT and c.3061C>T The patient had oral leukoplakia and hyperkeratotic verrucous papules on both soles. No cancer history despite the truncating mutation at age 21. NM_004260.4(RECQL4):c.3061C>T (p.Arg1021Trp), NM_004260.4(RECQL4):c.2059-76_3204del PubMed
A 13-month-old female with RTS RECQL4: c.2269C>T, c.1048_1049del Patient presented with facial rash, blisters, hypoplastic thumbs, frontal bossing, fine hair, short stature, and absent eyelashes/eyebrows. Radiographic analysis showed radial ray defect, absence of the thumb and three wrist carpal bones, and reduced bone density. NM_004260.4(RECQL4):c.2269C>T (p.Gln757Ter), NM_004260.4(RECQL4):c.1048_1049del (p.Arg350fs) PubMed
Two siblings with a mild phenotype RECQL4: c.2272C>T and c.2492_2493delAT Rothmund-Thomson syndrome with poikiloderma, sparse hair, eyelashes and/or eyebrows, small stature, skeletal and dental abnormalities and cancer predisposition NM_004260.4(RECQL4):c.2492_2493del (p.His831fs), NM_004260.4(RECQL4):c.2272C>T (p.Arg758Ter) PubMed
A patient with poikiloderma, severe osteoporosis and a mild intellectual disability and his brother RECQL4; c.1048_1049delAG and c.1391-1G>A Calcification cutis, osteoma cutis, poikiloderma, skeletal abnormalities (COPS) syndrome; Hodgkin's lymphoma NM_004260.4(RECQL4):c.1391-1G>A, NM_004260.4(RECQL4):c.1048_1049del PubMed
Five families exemplifying clinical and allelic heterogeneity of Rothmund-Thomson type-II syndrome (RTS-II) Biallelic mutations in RECQL4 gene Complete phenotype of patients #39 and #42 whose affected siblings developed osteosarcoma correlates with c.[1048_1049del], c.[1878+32_1878+55del], c.[1568G>C;1573delT], c.[3021_3022del] variants which damage the helicase domain. Patients #29 and #19 have a mild phenotype and carry, respectively, the unreported homozygous c.3265G>T and c.3054A>G variants, both sparing the helicase domain. Patient #38 is heterozygous for c.2412_2414del and no pathogenic CNVs out of those evidenced by high-resolution CGH-array, emerged as contributors to her phenotype. NM_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del), NM_004260.4(RECQL4):c.1568G>C (p.Ser523Thr), NM_004260.4(RECQL4):c.1568_1573delinsCCCCC (p.Ser523fs), NM_004260.4(RECQL4):c.3236G>T (p.Ser1079Ile) PubMed
14-year-old white boy with RTS type II RECQL4 gene mutations: compound heterozygous alleles Poikiloderma, skeletal abnormalities, sparse hair, absent or scanty eyelashes and eyebrows, short stature; developed osteosarcoma at age 10 NM_004260.4(RECQL4):c.1568G>C (p.Ser523Thr), NM_004260.4(RECQL4):c.1568_1573delinsCCCCC (p.Ser523fs) PubMed
Two siblings from a Portuguese family RECQL4:c.2492_2493del (p.His831fs) Diagnosed with osteosarcoma and Rothmund-Thomson syndrome NM_004260.4(RECQL4):c.2492_2493del (p.His831fs) PubMed
Patient with RTS type 2 RECQL4 mutation Diagnosed with osteosarcoma in the right femur at 6 years of age, developed a second OS in the contralateral femur 10 years later   PubMed
55-year-old male diagnosed with Bloom Syndrome during childhood RECQL4 gene (c.2269C>T and c.2547_2548delGT) Physical features such as short stature, chronic facial erythema, poikiloderma in face and extremities, microtia and microcephaly. Developed a calcaneal osteosarcoma NM_004260.4:c.2269C>T (p.Gln757Ter), NM_004260.4:c.2547_2548delGT (p.Phe850ProfsTer?) PubMed
A 31-year-old male with Cowden syndrome (CS) Germline mutations in PTEN and RecQ like helicase 4 (RECQL4) genes Synchronous follicular thyroid carcinoma (FTC) and papillary thyroid carcinoma (PTC) in a background of multiple follicular adenomatous nodules - PubMed

Cohort Based Reports

Cohort Setup Outcome HGVS(es) Citation
33 RTS patients (age range = 1-30 years), international cohort Mutations in the RECQL4 gene sequencing all 21 exons and 13 short introns from the genomic DNA of all subjects Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test). NM_004260.4(RECQL4):c.2269C>T (p.Gln757Ter), NM_004260.4(RECQL4):c.2492_2493del (p.His831fs), NM_004260.4(RECQL4):c.1573del (p.Cys525fs), NM_004260.4(RECQL4):c.1391-1G>A, NM_004260.4(RECQL4):c.3056-2A>C, NM_004260.4(RECQL4):c.1704+1G>A, NM_004260.4(RECQL4):c.806G>A (p.Trp269Ter), NM_004260.4(RECQL4):c.2059-1G>A, NM_004260.4(RECQL4):c.2476C>T (p.Arg826Ter), NM_004260.4(RECQL4):c.3072del (p.Val1026fs), NM_004260.4(RECQL4):c.2464-1G>C PubMed
Case-control study of lung and H-N cancers in smokers Genotype analysis of 30 genes involved in repair of DSB and in DNA damage response Potential associations between lung cancer and RECQL4 and RAD52 genes, as well as between H-N cancer and DNA-PK gene NM_004260.4(RECQL4):c.3502+24G>C, NM_004260.4(RECQL4):c.132A>G (p.Glu44=) PubMed
Six clinically diagnosed RTS patients Analysis of RECQL4 gene mutations Five patients with eight mutations mainly located in the helicase domain, three patients presenting two mutations, seven RECQL4 polymorphisms identified NM_004260.4(RECQL4):c.2221G>A (p.Ala741Thr), NM_004260.4(RECQL4):c.2780T>G (p.Leu927Arg) PubMed
22 human osteosarcoma tumors with differential response to chemotherapy, and 5 normal human osteoblasts Assess relative expression levels of 16 genes as potential biomarkers of osteosarcoma oncogenesis and chemotherapy response in human tumors using quantitative expression analysis RECQL4, SPP1, RUNX2, and IBSP were significantly overexpressed - PubMed
138 glioblastoma patients from Sweden and Denmark, and an additional 121 patients from the UK Relationship between 1458 SNPs capturing common genetic variation in 136 DNA repair genes and patient outcome in glioma 9 SNPs annotating MSH2, RAD51L1, and RECQL4 significantly associated with glioblastoma survival (p<0.05) NM_004260.4(RECQL4):c.3393+8C>T, NM_014665.4(LRRC14):c.-111-381G>C PubMed
Patients with Rothmund-Thomson syndrome (RTS) and Li-Fraumeni syndrome (LFS) Germline mutations in RECQL4 and p53 Lack of RECQL4 and p53 leads to increased mitochondrial genome instability associated with aging and/or cancer - 24067899
4435 pediatric cancer patients at St. Jude Children's Research Hospital and 1127 from the National Cancer Institute Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database, 249 with osteosarcoma Investigated whether heterozygous variants in RECQL4 are associated with increased risk for childhood cancer Identified 24 (0.43%) pediatric cancer patients with heterozygous RECQL4 loss-of-function variants, including five of 249 (2.0%) with osteosarcoma. RECQL4 variants were significantly overrepresented in children with OS as compared to noncancer controls. Nine of the 24 (38%) individuals possessed the same c.1573delT (p.Cys525Alafs) variant located in the highly conserved DNA helicase domain, suggesting that disruption of this domain is central to oncogenesis NM_004260.4(RECQL4):c.1573del (p.Cys525fs), NM_004260.4(RECQL4):c.2412_2420del (p.Ala805_Arg807del) PubMed
Multiple clinical syndromes with developmental abnormalities and high cancer risks RECQ4 mutations linked to three clinical diseases and high cancer risks were studied using molecular and biochemical properties of the RECQ4 protein Defining molecular dysfunctions of different RECQ4 disease mutations is imperative to improving our understanding of RECQ4 clinical phenotypes and the dynamic roles of RECQ4 in cancer development and prevention - PubMed


This blog article summarizes the growing body of evidence highlighting the association between RECQL4 mutations and osteosarcoma. By examining multiple research studies, we explore the impact of RECQL4 gene mutations on the incidence, progression, and prognosis of osteosarcoma. Notably, RECQL4 loss-of-function variants, particularly those affecting the DNA helicase domain, have been consistently implicated in the development of this aggressive bone cancer. Understanding the underlying molecular mechanisms can provide insights into potential therapeutic strategies and improved patient outcomes.


The accumulating evidence supports a significant connection between RECQL4 mutations and osteosarcoma. The high prevalence of RECQL4 loss-of-function variants, especially those affecting the DNA helicase domain, underscores the central role of RECQL4 dysfunction in osteosarcoma oncogenesis. Further research is warranted to unravel the precise mechanisms by which RECQL4 mutations contribute to osteosarcoma development and progression. Ultimately, a deeper understanding of RECQL4-related osteosarcoma can pave the way for targeted therapies and personalized treatment approaches in the fight against this challenging cancer.