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RECQL4 variants

Source: Childhood Cancer Genomics (PDQ®)–Health Professional Version, National Cancer Institute.

Source updated: April 30, 2025 · Captured 2026-09-09.

Selected source text with whitespace normalised. This Triangle page is not an NCI PDQ summary. Independent clinical review is pending.

Context: Sarcomas / Osteosarcoma / Molecular Features of Osteosarcoma / Genetic predisposition to osteosarcoma

Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children’s Research Hospital and 1,127 patients from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function RECQL4 variants, including 5 of 249 patients (2.0%) with osteosarcoma.[15] These RECQL4 variants were significantly overrepresented in children with osteosarcoma, the cancer most frequently observed in patients with Rothmund-Thomson syndrome, compared with 134,187 noncancer controls in the Genome Aggregation Database (gnomAD v2.1; P = .00087; odds ratio, 7.1; 95% confidence interval, 2.9–17). Nine of the 24 individuals (38%) 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.

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Table 5. Genetic Diseases That Predispose to Osteosarcomaa
Syndrome	Description	Location	Gene	Function
AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.
aAdapted from Kansara et al.[16]
Bloom syndrome [17]	Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.	15q26.1	BLM	DNA helicase
Diamond-Blackfan anemia [18]	Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes).		Ribosomal proteins	Ribosome production [18,19]
Li-Fraumeni syndrome [20]	Inherited variant in TP53 gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.	17p13.1	TP53	DNA damage response
Paget disease [21]	Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.	18q21-qa22	LOH18CR1	IL-1/TNF signaling; RANKL signaling pathway
		5q31
		5q35-qter
Retinoblastoma [22]	Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell variants at greater risk of subsequent neoplasms.	13q14.2	RB1	Cell-cycle checkpoint
Rothmund-Thomson syndrome (also called poikiloderma congenitale) [23,24]	Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.	8q24.3	RECQL4	DNA helicase
Werner syndrome [25]	Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.	8p12-p11.2	WRN	DNA helicase; exonuclease activity

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For more information about these genetic syndromes, see the following summaries:

Genetics of Breast and Gynecologic Cancers (Li-Fraumeni syndrome [LFS]).

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Genetics of Skin Cancer (Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome).

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For information about the treatment of osteosarcoma, see Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment.

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Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment

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Preserved source evidence · Independent clinical review pending · Not medical advice