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Werner Syndrome

, MD, PhD, , MD, and , MD.

Author Information
, MD, PhD
Department of Pathology
University of Washington
Seattle, Washington
, MD
Department of Pathology and Genome Sciences
University of Washington
Seattle, Washington
, MD
Division of Medical Genetics
Department of Medicine
University of Washington
Seattle, Washington

Initial Posting: ; Last Update: March 27, 2014.


Disease characteristics. Werner syndrome is characterized by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first sign is the lack of a growth spurt during the early teen years. Early findings (usually observed in the 20s) include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Myocardial infarction and cancer are the most common causes of death; the mean age of death in individuals with Werner syndrome is 54 years.

Diagnosis/testing. Clinical diagnostic criteria have been proposed. Biallelic pathogenic variants in WRN, the only gene known to be associated with Werner syndrome, are identified in approximately 90% of individuals with Werner syndrome.

Management. Treatment of manifestations: Aggressive treatment of skin ulcers; control of type 2 diabetes mellitus (pioglitazone has been successful); cholesterol-lowering drugs if lipid profile is abnormal; surgical treatment of ocular cataracts using special techniques; treatment of malignancies in a standard fashion.

Prevention of secondary complications: Smoking avoidance, regular exercise, weight control to reduce atherosclerosis risk; excellent skin care and avoidance of trauma to the skin.

Surveillance: Screening for type 2 diabetes mellitus at least annually; annual lipid profile; at least annual physical examination with attention to malignancies common in Werner syndrome; annual ophthalmologic examination for cataracts; attention to signs of angina.

Agents/circumstances to avoid: Smoking and excess weight, which increase the risk for atherosclerosis; trauma to the extremities.

Genetic counseling. Werner syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier. Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.


The diagnosis of Werner syndrome should be considered in individuals who have the following cardinal signs [Friedrich et al 2010]:

  • Bilateral ocular cataracts (present in 99%)*
  • Premature graying and/or thinning of scalp hair (100%)
  • Characteristic dermatologic pathology (96%)
  • Short stature (95%)

Approximately 91% of affected individuals have all four cardinal signs.

The clinical diagnosis may be further supported by the presence of the following signs and symptoms:

  • Thin limbs (present in 98%)
  • Pinched facial features (96%)
  • Osteoporosis (91%)
  • Voice change (89%)
  • Hypogonadism (80%)
  • Type 2 diabetes mellitus (71%)
  • Soft tissue calcification (67%)
  • Neoplasm(s) (44%)
  • Atherosclerosis (30%)
  • All four cardinal signs (91%)

* Note: Percent frequencies are derived from individuals with molecularly confirmed Werner syndrome at the time of diagnosis (i.e., individuals referred to the International Registry of Werner Syndrome).

Several sets of diagnostic criteria have been proposed [Nakura et al 1994, Takemoto et al 2013]; these also include the above four cardinal signs.

The diagnosis of Werner syndrome can be confirmed by detection of biallelic WRN pathogenic variants [Yu et al 1996]. See Table 1.

Evidence for locus heterogeneity. To date no other loci associated with typical forms of Werner syndrome have been identified, but it is theoretically possible that mutation of genes encoding proteins that interact with WRN may produce a similar phenotype.

One approach for molecular diagnosis of a proband suspected of having Werner syndrome is sequence analysis of WRN followed by deletion/duplication analysis if neither or only one pathogenic variant is identified.

An alternative approach is use of a multi-gene panel that includes WRN and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Table 1. Summary of Molecular Genetic Testing Used in Werner Syndrome

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
WRNSequence analysis 2~90% 3, 4
Deletion/duplication analysis 5Unknown 6
Protein analysis 7Not applicable

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Sequence analysis of the WRN coding region detects biallelic pathogenic variants in approximately 90% of affected individuals. The most common pathogenic variant, c.1105C>T, accounts for 20%-25% of pathogenic variants in the European and Japanese populations [Matsumoto et al 1997, Friedrich et al 2010]. Founder mutations have been identified in other populations (see Table 2).

4. Deep intronic pathogenic variants that affect splicing [Friedrich et al 2010] would not be detected by routine genomic sequencing analysis.

5. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. Reported pathogenic variants that require deletion/duplication analysis for detection include deletion and duplication of exon(s) [Friedrich et al 2010, Table A. Genes and Databases (see LSDB and HGMD)]. Pathogenic variants that occur in an intron and create a new exon as well as multiexonic deletions and duplications have also been reported [Huang et al 2006, Uhrhammer et al 2006, Friedrich et al 2010].

7. In the majority of affected individuals, WRN pathogenic variants result in the absence of Werner syndrome ATP-dependent helicase on western blot analysis (a truncated protein may be detected in rare cases) or immunoblot analysis [Shimizu et al 2002, Muftuoglu et al 2008]. Protein analysis may be useful in certain instances in combination with sequencing analysis, for example: 1) When only one mutant allele that is known to result in absence of protein is identified by sequencing. If protein analysis failed to detect protein, it would be inferred that the second unidentified allele also either fails to produce or alters the protein, thereby providing strong evidence for a diagnosis of WS. 2) When compound heterozygosity is identified where one allele is known to confer absence of protein but a second missense variant is of uncertain clinical significance. 3) Rarely, protein analysis may reveal that a missense variant of uncertain significance confers protein instability, which would define it as a pathogenic allele.

Test characteristics. Information on test sensitivity and specificity as well as other test characteristics can be found at EuroGentest [Hisama et al 2012 (full text)].

Click here for information on testing that is not currently available clinically.

Clinical Description

Natural History

Werner syndrome is characterized clinically by the premature appearance of features associated with normal aging and cancer predisposition. Individuals with Werner syndrome develop normally until the end of the first decade. The first symptom, often recognized retrospectively, is the lack of a growth spurt during the early teen years.

Symptoms typically start in the 20s. Initial findings include loss and graying of hair, hoarseness, and scleroderma-like skin changes, followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, skin ulcers, and osteoporosis in the 30s. Median age of onset of cataracts is approximately 31 years [Epstein et al 1966, Huang et al 2006]. A characteristic facial appearance, termed "bird-like" because of the pinched appearance at the bridge of the nose, evolves during the third or fourth decade. Median age of diagnosis ranges from late 30s to 40s [Epstein et al 1966, Tollefsbol & Cohen 1984, Goto 1997, Huang et al 2006].

Male to female ratio. The male:female ratio is believed to be 1:1. In the International Registry of Werner Syndrome, women are slightly over-represented, probably because of ascertainment bias: women are more likely than men to present for medical care and tend to have more concern about a youthful appearance.

Cardiovascular. Affected individuals exhibit several forms of arteriosclerosis; the most serious form, coronary artery atherosclerosis, may lead to myocardial infarction which, together with cancer, is the most common cause of death. The mean age of death in individuals with Werner syndrome is 54 years [Huang et al 2006]. Similarly the median life span of Japanese individuals with Werner syndrome is 53 years [Goto & Matsuura 2008].

Malignancy. The spectrum of cancers in individuals with Werner syndrome is unusual in that it includes a large number of sarcomas and very rare cancer types in typical locations [Goto et al 1996, Yamamoto et al 2003]. The most common cancers in Japanese individuals (for whom the most data exist) are soft-tissue sarcomas, osteosarcomas, melanomas, and thyroid carcinomas. Acral lentiginous melanomas (most often observed on the feet and nasal mucosa) are particularly prevalent compared to levels observed in the general population [Goto et al 1996]. Common types of carcinomas have also been observed.

Osteoporosis. The osteoporosis of individuals with Werner syndrome is unusual in that it especially affects the long bones. In contrast, osteoporosis during normative aging preferentially involves the vertebral bodies, particularly in women. Characteristic osteolytic lesions of the distal joints of the fingers are observed on radiograph.

Skin. Deep, chronic ulcers around the ankles (Achilles tendon, medial malleolus, lateral malleolus) are highly characteristic.

Neurologic. Controversy exists concerning the degree to which the brain is involved. While individuals with Werner syndrome may have central nervous system complications of arteriosclerosis, they do not appear to be unusually susceptible to Alzheimer disease [Martin et al 1999]. Cognitive changes are not typically observed. Diffuse changes observed on brain MRI in some individuals warrant further investigation in research studies [De Stefano et al 2003].

Fertility. Fertility appears to decline soon after sexual maturity. This decline in fertility is associated with testicular atrophy and probable accelerated rate of loss of primordial follicles in the ovaries, although data are sparse. Early menopause is common in women as are multiple miscarriages, but successful pregnancies have also been reported. Men have fathered children, usually at younger ages than in the general population [Epstein et al 1966].

Genotype-Phenotype Correlations

The chronologic order of the onset of signs and symptoms is similar in all individuals with Werner syndrome regardless of the specific WRN pathogenic variants [Epstein et al 1966, Tollefsbol & Cohen 1984, Goto 1997].

The specific cell type in which cancer develops may depend on the type of WRN pathogenic variant present. In individuals of Japanese descent, papillary thyroid carcinoma has been associated with an N-terminal mutation, whereas follicular thyroid carcinoma is more frequently observed with a C-terminal mutation [Ishikawa et al 1999]. This finding clearly contradicts the original assumption that all identified WRN pathogenic variants result in truncation of the nuclear localization signal of WRN protein and thereby act as null mutations. Further studies may reveal additional genotype-phenotype correlations.


Another name for Werner syndrome is 'progeria of the adult' (to distinguish it from the Hutchinson-Gilford progeria syndrome, which is often referred to as progeria of childhood).


The prevalence of Werner syndrome varies with the level of consanguinity in populations.

In the Japanese population, the frequency ranges from about 1:20,000 to 1:40,000, based on the frequencies of detectable heterozygous pathogenic variants [Satoh et al 1999]. This is most likely the result of a founder mutation in the Japanese population. Similarly, in the Sardinian population, the frequency is estimated at 1:50,000 [Masala et al 2007].

The prevalence in the US population is unknown, but may be on the order of 1:200,000 [Martin et al 1999].

Differential Diagnosis

The differential diagnosis depends on the presenting symptoms and age of onset.

  • Atypical Werner syndrome characterizes a small subset of individuals in the Werner Syndrome Registry who have normal WRN protein and some signs and symptoms that sufficiently overlap with the Werner syndrome such that clinicians submit their cases to the International Registry. These individuals typically have comparatively early age of onset (early 20s or earlier) and a faster rate of progression of symptoms than those with typical Werner syndrome. Among this group, four of 26 individuals (15%) had novel heterozygous pathogenic missense variants in LMNA [Chen et al 2003].
  • Mandibulo-acral dysplasia (MAD) is a progeroid syndrome characterized by short stature; type A lipodystrophy with loss of fat in the extremities but accumulation of fat in the neck and trunk; thin, hyperpigmented skin; partial alopecia; prominent eyes; beaked nose; tooth loss; small recessed chin; and short fingers [Cavallazzi et al 1960, Cohen et al 1973]. Mutation of LMNA has been reported by Novelli et al [2002] and Cao & Hegele [2003]. MAD with a generalized loss of subcutaneous fat (termed type B lipodystrophy) and insulin resistance has been attributed to compound heterozygous pathogenic variants in the zinc metalloproteinase ZMPSTE24 [Agarwal et al 2003].
  • Hutchinson-Gilford progeria syndrome (HGPS, progeria of childhood), like Werner syndrome, affects multiple organs with presentations characterized as accelerated aging. Newborns with HGPS usually appear normal, but profound failure to thrive occurs during the first year. Characteristic facies, partial alopecia progressing to total alopecia, loss of subcutaneous fat, progressive joint contractures, bone changes, and abnormal tightness and/or small soft outpouchings of the skin over the abdomen and upper thighs usually become apparent during the second to third year. Motor and mental development is normal. Individuals with HGPS develop severe atherosclerosis. Death usually occurs as a result of complications of cardiac or cerebrovascular disease generally between age six and 20 years. Average life span is approximately 13 years. Classic Hutchinson-Gilford progeria syndrome is defined by the presence of the LMNA pathogenic variant c.1824C>T. Inheritance is autosomal dominant. In all individuals with HGPS the mutation is de novo.
  • Early-onset type 2 diabetes with secondary complications of vascular disease and skin complications could mimic some features of Werner syndrome.
  • Though bilateral ocular cataracts (probably presenting as posterior subcapsular cataracts) are one of the most commonly observed features of Werner syndrome, the age of onset is typically in the second decade when graying of hair and skin findings would likely be present. Isolated juvenile cataracts are therefore not likely to be a feature of Werner syndrome. Myotonic dystrophy type 1 or myotonic dystrophy type 2 could be a consideration with young adult-onset cataracts, and adults may show muscle wasting, although other manifestations (e.g., myotonia or cardiac conduction abnormalities) are quite different and onset is usually in adulthood.
  • Scleroderma, mixed connective tissue disorders, and lipodystrophy may have skin features similar to those of Werner syndrome. Distal atrophy and skin ulcerations in the absence of other manifestations characteristic of Werner syndrome could raise the possibility of Charcot-Marie-Tooth disease or familial leg ulcers of juvenile onset.
  • Other cancer-prone syndromes including Rothmund-Thomson syndrome (RTS) (caused by mutation of RECQL4) and Bloom syndrome (caused by mutation of BLM) may be considered if cancer is the presenting symptom. However, RTS and Bloom syndrome are childhood-onset disorders. Werner syndrome cells do not exhibit the increased sister chromatid exchange typical of Bloom syndrome. Li-Fraumeni syndrome (caused by mutation of TP53) may present with multiple cancers, including non-epithelial cancers similar to those observed in Werner syndrome, but juvenile-onset cataracts and other manifestations of Werner syndrome are not part of Li-Fraumeni syndrome.

The following conditions share at least two features of Werner syndrome, but are less likely to be confused with the condition because they are characterized by onset in childhood and additional characteristic features:

  • The Flynn-Aird syndrome includes cataracts combined with skin atrophy and ulceration; neurologic abnormalities are also present [Flynn & Aird 1965].
  • The branchiooculofacial syndrome is characterized by premature graying in adults. Eye findings typically include strabismus, coloboma, and micropthalmia. Dysmorphic facial features are also present.
  • The SHORT syndrome (short stature, hyperextensibility, hernia, ocular depression, Rieger anomaly, and teething delay) may have progeria-like facies and lipodystrophy. Type 2 diabetes mellitus, as well as cataracts and glaucoma, has been reported in affected individuals [Schwingshandl et al 1993, Sorge et al 1996].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Werner syndrome, the following evaluations are recommended:

  • Screen for type 2 diabetes mellitus by standard clinical assays including fasting glucose level, hemoglobin A1c, or oral glucose tolerance test
  • Lipid profile
  • Physical examination for cancers common in Werner syndrome, (e.g., thyroid nodules, skin tumors)
  • Ophthalmologic examination including slit lamp examination
  • Skin examination for common findings, especially early ulcerations of the feet, with special attention to nail beds and soles of feet for lentiginous melanoma
  • Head MRI if neurologic symptoms including new onset seizures, focal neurologic signs such as weakness or visual field defect, or symptoms such as diploplia or headache are present. These can be indicative of meningioma, a common neoplasm in Werner syndrome.
  • Assessment of coping and psychological fitness in light of prognosis
  • Medical genetics consultation

Infants with Werner syndrome are unaffected at birth; thus, no special precautions or investigations are recommended in the neonatal period.

Treatment of Manifestations

The following are appropriate:

Prevention of Secondary Complications

To prevent secondary complications:

  • Lifestyle counseling for smoking avoidance, regular exercise, and weight control to reduce atherosclerosis risk
  • Excellent skin care, trauma avoidance, and examination to treat problems early


Appropriate surveillance includes the following:

  • Screening for type 2 diabetes mellitus at least annually
  • Annual lipid profile
  • At least annual physical examination for malignancies common in Werner syndrome and other skin manifestations
  • Annual ophthalmologic examination for cataracts
  • Attention to symptoms of angina, or peripheral or cerebrovascular disease

Agents/Circumstances to Avoid

Smoking and excess weight increase the risk of atherosclerosis.

Trauma to the extremities should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In one study of individuals with Werner syndrome, signs of hypogonadism were reported in 80%; however, approximately half of those had children and showed signs of hypogonadism after age 30 years [Goto 1997]. Reports in the medical literature of pregnancy in individuals with WS are rare, but in the International Registry of Werner Syndrome, many of the women have had offspring. Preterm delivery has been reported in several cases, and has been attributed to cervical incompetence. Preeclampsia is another reported obstetric complication [Murakami et al 2003].

The use of assisted reproductive technologies such as in vitro fertilization and egg donation has not been reported in women with Werner syndrome.

Therapies Under Investigation

Search for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.


Affected individuals may benefit from reproductive advice regarding the rapid decline in fertility.

Although topical PDGF-BB has been shown to provide some improvement of granulation, it failed to heal the ulcer in a person with Werner syndrome [Wollina et al 2004].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Werner syndrome is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • Parents of a proband are obligate heterozygotes for a pathogenic variant and therefore carry one mutant allele.
  • Although systematic clinical studies have not been reported, heterozygotes do not appear to be at increased risk for any Werner syndrome-specific symptoms.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being neither affected nor a carrier.
  • Once an at-risk sib is known to be unaffected, the chance of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with Werner syndrome are obligate heterozygotes for a pathogenic variant. Due to the very low prevalence in the US population, the risk for Werner syndrome in the offspring of an affected individual is negligible unless the affected individual and his/her reproductive partner are consanguineous. In Japan, where heterozygotes may be as common as one in 150, the risk for Werner syndrome in an offspring is still less than 1/500.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Carrier testing using molecular genetic techniques is possible if the WRN pathogenic variants have been identified in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Werner Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Werner Syndrome (View All in OMIM)


Molecular Genetic Pathogenesis

The mechanism by which WRN pathogenic variants cause the Werner syndrome phenotype is not clear. WRN encodes a multifunctional nuclear protein of 1,432 amino acids [Yu et al 1996] that is a member of the RecQ family of DNA helicases. The N-terminal region of the protein encoded by WRN has exonuclease activity as well.

DNA-type helicases are ATP-dependent 3'→ 5' helicases that are necessary to maintain genomic integrity in cells. Other human RecQ helicases are encoded by RECQL, BLM (responsible for the Bloom syndrome), RECQL4 (responsible for the Rothmund-Thomson syndrome), and RecQL5 [reviewed by Bohr 2008].

The WRN helicase preferentially unwinds DNA structures, such as tetraplex DNA, double-strand DNA with mismatch "bubbles," and Holliday junctions. It unwinds DNA-DNA double strands as well as DNA-RNA double strands. WRN exonuclease activity also preferentially digests single strands in complex DNA structures, such as double-stranded DNA with mismatched ends or bubbles. WRN helicase and exonuclease activities are modified by binding to interacting proteins (e.g., Ku complex, p53, replication protein A) and by phosophorylation [Bohr 2008, Rossi et al 2010].

Biochemical and cell biologic studies suggest that WRN protein is involved in DNA repair, recombination, replication, and transcription as well as combined functions such as DNA repair during replication. WRN protein can potentially unwind or digest aberrant DNA structures accidentally generated during various DNA metabolisms and also regulate DNA recombination and repair processes by unwinding or digesting intermediate DNA structures. WRN protein is also involved in the maintenance of telomeres. These findings are consistent with the notion that WRN plays a role in maintenance of genomic stability [Bohr 2008, Rossi et al 2010].

Gene structure. WRN has a transcript of 5765 bp and consists of 35 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Variants of unknown significance. The allelic variant of unknown significance c.2500C>T was found in populations of Spanish ancestry with a heterozygote frequency of 0.007. This change abolishes helicase and exonuclease activities in vitro. Homozygous individuals could exhibit some of the phenotypes of WS, but this has not been demonstrated [Kamath-Loeb et al 2004].

Pathogenic allelic variants. More than 70 different WRN pathogenic variants have been identified. The majority of pathogenic variants are stop codons, insertions, or deletions that result in a frame shift or splice donor or acceptor site mutations that result in exon skipping. Several missense variants that abolish helicase activity or confer protein instability have been reported.

Pathogenic variants that occur in an intron and result in creation of a new exon as well as multiexonic deletions and duplications have also been reported [Huang et al 2006, Uhrhammer et al 2006, Friedrich et al 2010].

The most common pathogenic variant is c.1105C>T, which accounts for 20%-25% of pathogenic variants in the European and Japanese populations [Matsumoto et al 1997, Friedrich et al 2010].

Founder mutations have been reported in some populations (Table 2).

While protein analysis does not distinguish different types of pathogenic variants, it provides important supportive evidence. For example, the Sardinian founder mutation, c.2089-3024A>G, is an intronic mutation that creates a new exon resulting in a protein of altered length.

Table 2. Selected WRN Variants

Variant ClassificationDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
Unknown significancec.2500C>Tp.Arg834CysNM_000553​.4
c.2089-3024A>G 1 See footnote 2
c.2179dupT 3p.Cys727LeufsTer5
c.3139-1G>C 4See footnote 5
c.3460-2A>C 6See footnote 7
c.3590delA 8p.Asn1197ThrfsTer2

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.

1. A founder mutation in the Sardinian population [Masala et al 2007]

2. Creates a new exon between exons 18 and 19 that introduces a stop codon and alters the length of the protein [Masala et al 2007]

3. Potential founder mutation in Moroccan population [Friedrich et al 2010]

4. Founder mutation in Japanese population accounts for approximately 60% of mutations in affected individuals of this group [Satoh et al 1999].

5. Results in exon 26 skipping

6. Potential founder mutation in Turkish population [Friedrich et al 2010]

7. Results in exon 30 deletion

8. Potential founder mutation in Dutch population [Friedrich et al 2010]

Normal gene product. The normal gene product has 1,432 amino acids. The central region of the WRN ATP-dependent helicase contains the consensus domains of RecQ type helicases [Gray et al 1997] and the N-terminal region contains exonuclease domains [Huang et al 1998]. A nuclear localization signal is at the C-terminal end of the protein [Suzuki et al 2001]. A highly acidic transactivation sequence is present between exonuclease and helicase domains [Balajee et al 1999]. There are two consensus domains in the C-terminal region whose functions have not been completely elucidated: a RecQ C-terminal conserved (RCQ) region and a helicase RNaseD C-terminal (HRDC) conserved region. The RCQ region, which contains a zinc finger motif and a winged helix motif (WH) may be involved in the regulation of helicase enzymatic activity by modulating DNA binding as well as protein folding of WRN helicase [Kitano et al 2010]. The HDRC region is speculated to mediate protein-protein interactions.

Abnormal gene product. A majority of pathogenic variants result in the truncation of the protein. In addition to the loss of the nuclear localization signal in WRN mutant proteins [Huang et al 2006], the mutant mRNAs and the resulting mutant proteins exhibit shorter half-lives than do the wild-type mRNA and WRN protein [Yamabe et al 1997].

Cancer and benign tumors. Cancerous tissues obtained from normal individuals commonly show alterated methylation status of the WRN promoter resulting in transcriptional silencing of WRN [Agrelo et al 2006]. Epigenetic inactivation of WRN would lead to increased chromosomal instability.


Literature Cited

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Chapter Notes

Author History

Nancy Hanson, MS; University of Washington (2002-2011)
Fuki M Hisama, MD (2011-present)
Dru F Leistritz, MS; University of Washington (2002-2011)
George M Martin, MD (2002-present)
Junko Oshima, MD, PhD (2002-present)

Author Notes

International Registry of Werner Syndrome
Phone: 206-543-5088
Fax: 206-685-6356
Web site:

Revision History

  • 27 March 2014 (me) Comprehensive update posted live
  • 13 December 2012 (cd) Revision: prenatal testing available clinically
  • 1 November 2012 (cd) Revision: deletion/duplication analysis available clinically
  • 9 February 2012 (cd) Revision: protein analysis clinically available
  • 29 December 2011 (cd) Revision: sequence analysis and carrier testing available clinically
  • 17 November 2011 (me) Comprehensive update posted live
  • 8 March 2007 (me) Comprehensive update posted to live Web site
  • 13 January 2005 (me) Comprehensive update posted to live Web site
  • 16 March 2004 (nh) Revision: Normal allelic variants
  • 2 December 2002 (me) Review posted to live Web site
  • 30 July 2002 (nh) Original submission
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