• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The RECQL4 gene is associated with autosomal recessive Rothmund-Thomson syndrome (MedGen UID: 10819), RAPADILINO syndrome (MedGen UID: 336602), and Baller-Gerold syndrome (MedGen UID: 120532).

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The RECQL4 gene encodes one of the RecQ DNA helicases, which unwinds double stranded DNA into single stranded DNA. This gene plays an important role in genome maintenance and stability by regulating DNA repair and replication and is ubiquitously expressed.

MedGen UID: 10819, 336602, 120532

Clinical condition
The RECQL4 gene is associated with Rothmund-Thomson syndrome (RTS), Baller-Gerold syndrome (BGS), and RAPADILINO syndrome (RAdial hypoplasia, PAtellae hypoplasia and cleft or arched PAlate, DIarrhea and DIslocated joints, LIttle size and LImb malformation, slender NOse and NOrmal intelligence; PMID: 11471165, 18716613, 15964893). While these rare conditions have distinct clinical characteristics, they share a number of overlapping features, including skeletal anomalies, growth deficiency, gastrointestinal disturbances, increased cancer risk, and normal intellect (PMID: 15964893).

Of all reported RECQL4-related conditions, most have been diagnosed as RTS (Genetics Home Reference. RECQL4 gene. https://ghr.nlm.nih.gov/gene/RECQL4. Accessed July 2017). The hallmark feature of this condition is a cutaneous rash, which typically presents between 3 and 6 months of age (PMID: 20113479). This acute rash is erythematous, with facial swelling and blistering that subsequently spreads to the extremities. The buttocks, trunk, and abdomen are often spared (PMID: 20113479). Over time, this rash develops into chronic poikiloderma, characterized by telangiectatic lesions, reticulated depigmented areas, hyperpigmentation, and punctate atrophy (PMID: 20113479). Other ectodermal features are variable and may include café-au-lait macules, palmoplantar hyperkeratosis, sparse or absent hair, premature aging, and underdeveloped or absent teeth and nails (PMID: 15964893, 20113479).

Growth deficiency is the second major clinical sign of RTS: low birth weight and failure to thrive are common (PMID: 15964893, 20113479). Affected individuals typically have symmetrical short stature in spite of normal growth hormone levels (PMID: 20113479).

A variety of gastrointestinal anomalies have also been described in individuals with RTS, including esophageal stenosis, pyloric stenosis, anal atresia, annular pancreas, and rectovaginal fistula (PMID: 8346112). Feeding problems may occur in infancy, with some requiring tube feeding (PMID: 20113479). Gastrointestinal symptoms often manifest as chronic emesis and diarrhea, typically resolving in childhood (PMID: 17372760).

In addition, RTS is associated with a number of skeletal findings. Frontal bossing and saddle nose are characteristic craniofacial features (PMID: 18647888). Skeletal abnormalities include radial ray defects, hypoplasia/agenesis of the patella, syndactyly, and osteoporosis (PMID: 18647888). Other subclinical findings require identification by radiograph, and include abnormal metaphyseal trabeculation, brachymesophalangy, thumb aplasia/hypoplasia, osteopenia, destructive bone lesions, radial head dislocation, radial aplasia/hypoplasia, and patellar ossification defects (PMID: 18647888).

RTS is associated with increased risk of cataracts, which are typically of rapid and juvenile onset (PMID: 1430398, 11471165, 20113479). Other reported ocular findings include exophthalmos, corneal atrophy/scleralization, congenital glaucoma, retinal atrophy, coloboma, strabismus, photophobia, and blue sclerae (PMID: 20113479).

An increased risk of various malignancies has also been described, most commonly osteosarcoma. Osteosarcoma in RTS is usually of juvenile onset, with average age of onset of 14 years (PMID: 18346259). There is an increased risk of non-melanoma skin cancers, such as squamous cell and basal cell carcinomas, typically diagnosed in adulthood with an average age of onset of 34 years (PMID: 18346259). In addition, there appears to be an association with hematologic malignancies such as myelodysplasia, aplastic anemia, and leukemia (PMID: 11471165, 18346259). While lifetime cancer risks are not well established, one cohort study reported osteosarcoma in approximately 30% of affected individuals and non-melanoma skin cancers in roughly 5% (PMID: 11471165, 18346259). Life expectancy in the absence of malignancy and with appropriate medical care is usually normal (PMID: 20113479).

An increasing number of reports has suggested an association between RTS and susceptibility to immunodeficiency and infections such as bronchiectasis, bronchitis, and recurrent pneumonia (PMID: 26064716, 9568421, 17250521). In addition, cases of progressive leukopenia and chronic microcytic hypochromic anemia have been reported (PMID: 10606946, 11076043).

Infertility has been described in affected males and females; however, some affected females have had normal pregnancies, and a few males have produced offspring (PMID: 11471165).

RAPADILINO syndrome has significant clinical overlap with RTS; however, it is distinguished by joint dislocations and absence of cataracts and poikiloderma (PMID: 20113479, 20301415). An increased risk for cancer, specifically sarcoma and lymphoma, has been reported (PMID: 2801769, 18716613, 26064716).

BGS, the rarest of the RECQL4-associated disorders, is clinically distinguishable from RTS by the presence of coronal craniosynostosis and absence of cataracts (PMID: 20113479, 20301415). While some individuals with BGS may develop poikiloderma, it is unknown if BGS is associated with an increased risk for malignancy (PMID: 15964893, 18716613).

Gene Information
RECQL4 encodes DNA helicase Q4 and is a member of the RECQ gene family. RECQL4 is important in maintaining genomic stability and thought to be involved in multiple aspects of DNA replication, repair, and telomere maintenance (PMID: 20113479).

RECQL4-related conditions have autosomal recessive inheritance. Individuals with a single RECQL4pathogenic variant are considered unaffected carriers of RECQL4-related conditions. Each child with two carrier parents has a 1 in 4, or 25%, chance of inheriting both variants and being affected with a RECQL4-related condition.

Affected individuals have two pathogenic variants—one in each copy of their RECQL4 genes—and will pass one pathogenic RECQL4 variant on to all of their children. The risk of having an affected child depends upon whether or not their partner also carries a RECQL4 pathogenic variant.

Individuals with RECQL4-related conditions should be managed by a multidisciplinary team inclusive of a dermatologist, ophthalmologist, orthopedic surgeon, and an oncologist (PMID: 20113479). Surveillance should include annual physical exams by clinicians aware of the natural history of RECQL4-related conditions and the importance of long-term follow-up, with particularly careful monitoring for bone tumors (PMID: 20113479). Medical management recommendations for RTS have been proposed by Wang et al. (PMID: 11471165):


  • annual dermatologic evaluation for precancerous lesions
    • treatment of the telangiectatic component of the rash with pulsed dye laser photocoagulation (PMID: 1923988)
  • sun avoidance practices and use of UVA/UVB sunscreens


  • annual ophthalmologic evaluation to screen for cataracts
    • surgical removal of cataracts as needed


  • regular monitoring of growth (PMID: 20301415)
  • baseline skeletal radiographs of the long bones by 5 years of age
  • family education about signs and symptoms of osteosarcoma, including bone pain, swelling, and limb enlargement
  • prompt skeletal radiographic examination when clinical suspicion of osteosarcoma is present (PMID: 20301415)
    • standard treatment for those who develop cancer
  • calcium and vitamin D supplements may be warranted in individuals with osteopenia or a history of fractures (PMID: 20301415)


  • consideration of pulmonary function tests and computed tomography in individuals with respiratory symptoms to assess for bronchitis and bronchiectasis (PMID: 17250521)


  • baseline complete blood count (CBC) with differential (PMID: 20301415)
  • consideration of CBC and bone marrow biopsy for individuals with clinical evidence of anemia or cytopenias (PMID: 20301415)

In addition, due to multiple cases of immunodeficiency in RECQL4-related conditions, Vollebregt et al. have suggested consideration of immunological screening in affected individuals (PMID: 26064716).

Because RTS is considered a chromosome instability syndrome, there has been some debate whether affected individuals are particularly susceptible to ionizing and ultraviolet radiation (PMID: 18504617, 12734318). Concerns have been raised as to whether radiation exposure from osteosarcoma screening may be particularly carcinogenic (PMID: 18504617, 12734318). The data presented by Jin et al. showed modest radiation sensitivity in RECQL4-deficient fibroblasts compared with other chromosome instability syndromes such as ataxia-telangiectasia and xeroderma pigmentosa (PMID: 18504617). This evidence does not argue strongly for or against osteosarcoma screening (PMID: 18504617).

Likewise, there have been concerns that individuals with RECQL4-related conditions treated for malignancy may have chemotherapy hypersensitivity and an increased risk for a second malignancy (PMID: 17264332, 20503338). Second malignant disease has been described with risks ranging from 8% to 18% (PMID: 18346259, 17264332); however, data are limited. It appears that the affected individuals treated with chemotherapy do not experience significant toxicities, with the exception of mucositis with doxorubicin treatment (PMID: 17264332, 20503338, 18504617).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, as well as available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if pathogenic variants in RECQL4 are present is advantageous as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant RECQL4 data are likely to become available in the near future.

Awareness of this cancer predisposition allows patients and their providers to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information, to inform at-risk family members, and to consider implementing condition-specific screening suggestions.

Review date: July 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
RECQL4 NM_004260.3