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DDX11-Related Cohesinopathy

Synonyms: Warsaw Breakage Syndrome (WABS), Warsaw Syndrome

, MD, , PhD, and , MD.

Author Information and Affiliations

Initial Posting: ; Last Update: June 5, 2025.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

DDX11-related cohesinopathy is characterized by the clinical triad of severe congenital microcephaly, growth restriction, and sensorineural hearing loss due to cochlear hypoplasia. Intellectual disability is typically in the mild-to-moderate range. Severe speech delay is common. Gross and fine motor milestones are often attained at the usual time, although a few individuals have mild motor delays. Additional common features include skeletal and cardiovascular anomalies. Abnormal skin pigmentation and genitourinary malformations have also been reported. Some individuals have increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane and mitomycin C.

Diagnosis/testing.

The diagnosis of DDX11-related cohesinopathy is established in a proband with biallelic pathogenic variants in DDX11 identified by molecular genetic testing.

Management.

Treatment of manifestations: Supplementary formula and/or gastrostomy tube as needed to optimize nutrition. Treatments for hearing loss include hearing aids; cochlear implantation; auditory brain stem implant for individuals with profound hearing loss due to missing or nonfunctioning cochlea or auditory nerve; establishing a system of communication and hearing habilitation that may include sign language, auditory therapy, and speech therapy; and educational programs designed for individuals with hearing impairment. Early intervention and educational support; physical, occupational, and speech therapies; standard treatment for attention-deficit/hyperactivity disorder (ADHD); treatment of cardiac anomalies per cardiologist; treatment of limb anomalies per orthopedist with occupational therapy as needed; treatment of genitourinary anomalies per nephrologist and/or urologist.

Surveillance: Monitor growth, speech development, and educational needs with each visit; behavioral assessment for ADHD as needed; there is no consensus regarding tumor screening.

Genetic counseling.

DDX11-related cohesinopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a DDX11 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Once the DDX11 pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

Diagnosis

No consensus clinical diagnostic criteria for DDX11-related cohesinopathy have been published.

Suggestive Findings

DDX11-related cohesinopathy should be suspected in individuals with a triad of characteristic findings:

  • Congenital severe microcephaly
  • Prenatal and postnatal growth restriction
  • Congenital sensorineural hearing loss due to cochlear abnormalities (e.g., cochlear hypoplasia)

Additional clinical, imaging, and laboratory findings include the following.

Additional clinical findings

  • Intellectual disability and developmental delay
  • Skeletal anomalies (e.g., proximal insertion of the thumbs, shortening of the thumbs and the first metacarpals, clinodactyly of the fifth finger, and overlapping toes)
  • Abnormal skin pigmentation (e.g., café au lait macules, cutis marmorata, hypo- or hyperpigmentation, livedo reticularis with telangiectasia)
  • Congenital cardiovascular malformations (e.g., patent ductus arteriosus, atrial septal defect, ventricular septal defect, tetralogy of Fallot)
  • Genitourinary malformations (e.g., hypoplastic scrotum, cryptorchidism, hypospadias, multicystic kidneys)

Imaging findings. Cochlear anomalies on temporal bone imaging (e.g., cochlear hypoplasia)

Laboratory findings

  • Increased chromosome breakage and radial forms on cytogenetic testing of lymphocytes treated with diepoxybutane (DEB) and mitomycin C (MMC) in some affected individuals
    Note: The background rate of chromosome breakage in control chromosomes is more variable with MMC; thus, some centers prefer using DEB while other centers use both DEB and MMC.
  • Premature chromatid separation (PCS) and premature centromere division (PCD) – separation of the sister chromatids and centromeres during metaphase rather than in anaphase visible on C-banding techniques (See Figure 1.)
  • In many chromosomes, a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers
Figure 1. . C-banding of metaphase chromosomes in two individuals with DDX11-related cohesinopathy.

Figure 1.

C-banding of metaphase chromosomes in two individuals with DDX11-related cohesinopathy. Short arrows show chromosome morphology suggestive of premature centromere division (PCD); long arrows show chromosomes with premature chromatid separation (PCS). (more...)

Establishing the Diagnosis

The diagnosis of DDX11-related cohesinopathy is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in DDX11 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic DDX11 variants of uncertain significance (or of one known DDX11 pathogenic variant and one DDX11 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Option 1

When the phenotypic and laboratory findings suggest the diagnosis of DDX11-related cohesinopathy, molecular genetic testing approaches can include single-gene testing or use of a multigene panel:

  • Single-gene testing. Sequence analysis of DDX11 is performed first to detect missense, nonsense, and splice site variants and small intragenic deletions/insertions. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
    Note: Analysis of DDX11 is complicated by the presence of at least 16 highly homologous pseudogenes (e.g., DDX11L1, DDX11L2).
  • A multigene panel that includes DDX11 and other genes of interest (see Differential Diagnosis) may be considered to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants of uncertain significance in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) Given the rarity of DDX11-related cohesinopathy, some panels for microcephaly and/or hearing loss may not include this gene. (4) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (5) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Option 2

When the diagnosis of DDX11-related cohesinopathy is not considered because an individual has atypical phenotypic features, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

Note: Analysis of DDX11 is complicated by the presence of at least 16 highly homologous pseudogenes (e.g., DDX11L1, DDX11L2). Sequence for all exons of the gene may not be obtained by genomic testing.

For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in DDX11-Related Cohesinopathy

Gene 1MethodProportion of Pathogenic Variants 2 Identified by Method
DDX11 Sequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5None reported 4
1.
2.

See Molecular Genetics for information on variants detected in this gene.

3.

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

4.
5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

DDX11-related cohesinopathy is characterized by a clinical triad of severe microcephaly, growth restriction, and hearing loss. Other anomalies have also been described. To date, 26 individuals have been identified with biallelic pathogenic variants in DDX11 [van der Lelij et al 2010, Capo-Chichi et al 2013, Bailey et al 2015, Eppley et al 2017, Alkhunaizi et al 2018, Bottega et al 2019, Cortone et al 2018, Rabin et al 2019, van Schie et al 2020, Arroyo-Carrera et al 2023, Kratochwila et al 2024]. The following description of the phenotypic features associated with this condition is based on these reports.

Microcephaly has a prenatal onset and is reported in all affected individuals. Congenital microcephaly can range from 3.3 to 10 standard deviations (SD) below the mean for age and sex. Postnatal head growth velocity is slower than average for age and sex. However, there are no reports of a substantial decrease in head growth velocity in childhood.

Prenatal and postnatal growth deficiency. All 26 reported individuals to date had intrauterine growth deficiency with birth weight and height below the third centile. Postnatal growth deficiency was also reported in all individuals; two individuals had weights between the 50th and 75th percentile later in childhood, after they were started on gastrostomy tube feedings [Bailey et al 2015, Alkhunaizi et al 2018].

Congenital sensorineural hearing loss is usually severe and is due to bilateral hypoplasia of the cochlea and the cochlear nerve. Children with DDX11-related cohesinopathy usually present early with a failed newborn hearing screen or severe speech disability that is comparable to the degree of sensorineural hearing loss. Expressive language is consistently affected due to the hearing loss; receptive language is also involved but to a lesser degree. Sign language can be learned; however, due to the intellectual disability, this is also limited in some individuals along with receptive language.

Intellectual disability and developmental delay range from mild to moderate and tend to be stable. Gross and fine motor milestones are usually attained at the usual time although a few individuals have mild delays.

Behavioral issues such as mild attention-deficit/hyperactivity disorder (ADHD) and/or aggression were reported in a couple of individuals [Bailey et al 2015, Alkhunaizi et al 2018, van Schie et al 2020]; however, affected children usually have good interpersonal skills.

Skeletal anomalies are commonly seen (16/23 individuals), including proximal insertion of thumbs, shortened first metacarpals, small radii, syndactyly, and short thumbs.

Additional structural brain abnormalities. In addition to cochlear hypoplasia, one individual presented with posterior labyrinthine anomaly with persistent lateral semicircular canal anlage [Alkhunaizi et al 2018]. Eight individuals presented with brain anomalies including focal poor sulcation pattern, delayed gyration, focal lissencephaly, corpus callosum hypoplasia, and cerebellar vermis hypoplasia [Alkhunaizi et al 2018, Rabin et al 2019, van Schie et al 2020, Kratochwila et al 2024].

Cardiovascular anomalies are reported in 33% (7/21 individuals). These include patent ductus arteriosus (1), small atrial septal defect with large patent ductus arteriosus (1), ventricular septal defect (4), and tetralogy of Fallot (1).

Other manifestations reported in single individuals (or sibs):

  • Limb anomalies including fifth finger clinodactyly, brachydactyly, small fibula, talipes equinovarus, and overlapping toes
  • Abnormal skin pigmentation including café au lait macules, cutis marmorata, hypo- or hyperpigmentation, and livedo reticularis with telangiectasia
  • Genitourinary malformations including hypoplastic scrotum, cryptorchidism, hypospadias, and multicystic kidneys
  • Other findings including early menarche in two sisters [Eppley et al 2017] and seizure disorder in one individual [Alkhunaizi et al 2018]

Malignancy. DDX11 is essential for genome maintenance and may act as a tumor suppressor [Parish et al 2006]. The possibility of an increased risk of malignancy in obligate heterozygotes (parents) was raised by van der Lelij et al [2010], who reported a family that included a mother of the proband with lymphoma and another heterozygous relative with endometrial adenocarcinoma. None of the five affected individuals nor their parents reported by Alkhunaizi et al [2018] had cancer. Moreover, the oldest individual known to date with DDX11-related cohesinopathy died at age 64 years with no evidence of cancer [van Schie et al 2020]. Therefore, the risk of malignancy in individuals with DDX11-related cohesinopathy or heterozygous individuals remains unproven.

Genotype-Phenotype Correlations

No clinically relevant genotype-phenotype correlations are known.

Nomenclature

"Warsaw breakage syndrome" refers to the city of origin of the first reported individual and the elevated level of chromosome breakage, similar to Fanconi anemia, reported in some affected individuals [van der Lelij et al 2010].

The observation of inconsistent increased levels of chromosome breakage in individuals with this disorder led to the suggestion to change the name of the condition to Warsaw syndrome [Alkhunaizi et al 2018].

The designation "DDX11-related cohesinopathy" is based on the dyadic naming approach proposed by Biesecker et al [2021] to delineate mendelian genetic disorders.

Differential Diagnosis

Genetic disorders of interest in the differential diagnosis of DDX11-related cohesinopathy are listed in Table 2.

Table 2.

Disorders to Consider in the Differential Diagnosis of DDX11-Related Cohesinopathy

Gene(s)DisorderMOIFeatures of Disorder
Overlapping w/DDX11-related cohesinopathyDistinguishing from DDX11-related cohesinopathy
21 genes incl:
BRCA2
BRIP1
FANCA
FANCB
FANCC
FANCD2
FANCE
FANCF
FANCG
FANCI
RAD51
Fanconi anemia AR
AD
XL 1
  • Microcephaly
  • Growth deficiency, prenatal &/or postnatal short stature, low birth weight
  • Abnormal skin pigmentation: generalized hyperpigmentation, café au lait macules, hypopigmentation
  • Skeletal malformations of upper & lower limbs
  • Hearing loss (10% of affected persons) 2
  • Chromosome instability (chromosome breakage induced by DEB & MMC)
Progressive bone marrow failure w/pancytopenia
ESCO2 Roberts syndrome (See ESCO2 Spectrum Disorder.)AR
  • Mild-to-severe prenatal growth restriction
  • Hand anomalies
  • Cytogenetic findings of premature centromere separations
  • Bilateral symmetric tetraphocomelia or hypomelia
  • Elbow & knee flexion contractures
  • Ear malformations
  • Corneal opacities
  • Not assoc w/SNHL
NBN Nijmegen breakage syndrome AR
  • Microcephaly, progressive
  • Early growth deficiency (more pronounced from birth until age 2 years, w/mild improvement thereafter)
  • Chromosome instability (inversions & translocations involving chromosomes 7 & 14)
  • Immunodeficiency
  • Premature ovarian failure in females
  • ↑ risk of malignancy (primarily lymphoma)
  • Not assoc w/SNHL
PCNT Microcephalic osteodysplastic primordial dwarfism type II AR
  • Pre- & postnatal growth deficiency
  • Severe microcephaly
  • Short stature
  • Growth deficiency is more severe; extremely short stature
  • Lack of cochlear hypoplasia
  • CNS vascular anomalies
  • Insulin resistance
LIG4 LIG4 syndrome (OMIM 606593)AR
  • Microcephaly
  • Short stature
  • chromosome breakage rate
  • Hearing loss
  • Immunodeficiency, combined; pancytopenia & myelodysplastic syndrome
  • Predisposition to malignancy (mainly lymphoma & leukemia)

AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DEB = diepoxybutane; MMC = mitomycin C; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked

1.

Fanconi anemia (FA) is inherited in an autosomal recessive manner with the exception of RAD51-related FA (autosomal dominant inheritance) and FANCB-related FA (X-linked inheritance).

2.

Unlike DDX11-related cohesinopathy, hearing loss in FA is usually conductive.

Management

No clinical practice guidelines for DDX11-related cohesinopathy have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with DDX11-related cohesinopathy, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

DDX11-Related Cohesinopathy: Recommended Evaluations Following Initial Diagnosis

System/ConcernEvaluationComment
Constitutional Assessment of growth parametersTo identify those w/growth deficiency
ENT ENT referral & audiologic eval incl temporal bone imaging
Development/
Behavior
  • Assess speech development & intellectual abilities.
  • Assess for features of ADHD.
Esp important in toddlers & school-age children
Cardiovascular Cardiology eval w/echocardiogramTo evaluate for congenital cardiac anomalies
Orthopedic Assess for radial & other limb anomalies.
Genitourinary Assess for genitourinary anomalies, w/renal ultrasound.
Genetic counseling By genetics professionals 1To obtain a pedigree & inform affected persons & their families re nature, MOI, & implications of DDX11-related cohesinopathy to facilitate medical & personal decision making

ADHD = attention-deficit/hyperactivity disorder; MOI = mode of inheritance

1.

Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Table 4.

DDX11-Related Cohesinopathy: Treatment of Manifestations

Manifestation/
Concern
TreatmentConsiderations/Other
Poor weight gain / Growth deficiency
  • Optimize nutrition in those w/poor weight gain.
  • Supplementary formulas &/or gastrostomy tube as needed
Hearing loss
  • Hearing aids should be considered in those w/non-profound hearing loss.
  • Cochlear implantation, if cochlear nerve is present
  • Auditory brain stem implant (ABI) is an optional treatment. 1
  • Establish an appropriate system of communication & hearing habilitation immediately w/diagnosis of hearing loss; may include sign language in addition to auditory & speech therapy.
  • Offer educational programs designed for those w/hearing impairment.
Hearing aids are rarely beneficial if there is complete absence of cochlear nerve; however, an ABI may be beneficial for those w/profound hearing loss due to missing or nonfunctioning cochlea or auditory nerve.
Developmental delay
  • Early intervention & educational support as needed
  • Ongoing PT, OT, & speech therapy to optimize developmental outcomes
Behavioral issues Standard treatment for ADHD
Cardiac anomalies Treatment per cardiologist
Limb anomalies Treatment per orthopedist; OT as needed
Genitourinary anomalies Treatment per nephrologist &/or urologist

ADHD = attention-deficit/hyperactivity disorder; OT = occupational therapy; PT = physical therapy

1.

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Table 5.

DDX11-Related Cohesinopathy: Recommended Surveillance

System/ConcernEvaluationFrequency
Growth Monitor growth incl height, weight, head circumference, & body mass index.At each visit
Development Assess speech development & educational needs.
Neurobehavioral/
Psychiatric
Behavioral assessment for ADHDAs needed
Malignancy No consensus for tumor screening 1

ADHD = attention-deficit/hyperactivity disorder

1.

Although van der Lelij et al [2010] suggested an increased incidence of malignancies in first-degree relatives of individuals with DDX11-related cohesinopathy, to date no affected individuals have developed malignancies and most reported families do not have an increased incidence of malignancies. Thus, it is not known if DDX11-related cohesinopathy is associated with an increased incidence of malignancy and if surveillance for malignancies should be recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

DDX11-related cohesinopathy is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

Sibs of a proband

  • If both parents are known to be heterozygous for a DDX11 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
  • Heterozygotes (carriers) are not at risk of developing DDX11-related cohesinopathy. The possibility of an increased risk of malignancy in heterozygotes (parents/sibs of a proband) was raised by van der Lelij et al [2010]; however, the risk of malignancy in heterozygous individuals remains unproven (see Clinical Description, Malignancy).

Offspring of a proband. Unless the reproductive partner of an affected individual also has DDX11-related cohesinopathy or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in DDX11.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a DDX11 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the DDX11 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected children and young adults who are carriers or are at risk of being carriers.
  • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with DDX11-related cohesinopathy, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the DDX11 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Fetal imaging. Prenatal ultrasound findings in DDX11-related cohesinopathy may include intrauterine growth deficiency, microcephaly, delayed sulcation, short corpus callosum, and cerebellar vermis hypoplasia [Alkhunaizi et al 2018, Kratochwila et al 2024].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Resources

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.

  • Warsaw Breakage Syndrome Foundation
  • American Society for Deaf Children
    Phone: 800-942-2732 (ASDC)
    Email: info@deafchildren.org
  • Human Growth Foundation
  • MAGIC Foundation
    Phone: 630-836-8200
    Email: contactus@magicfoundation.org
  • National Association of the Deaf
    Phone: 301-587-1788 (Purple/ZVRS); 301-328-1443 (Sorenson); 301-338-6380 (Convo)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • Restricted Growth Association
    United Kingdom

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.

DDX11-Related Cohesinopathy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
DDX11 12p11​.21 ATP-dependent DNA helicase DDX11 DDX11 @ LOVD DDX11 DDX11

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for DDX11-Related Cohesinopathy (View All in OMIM)

601150DEAD/H-BOX HELICASE 11; DDX11
613398WARSAW BREAKAGE SYNDROME; WABS

Molecular Pathogenesis

DDX11 encodes ATP-dependent DNA helicase DDX11 (DDX11), which belongs to a family of human DNA helicases (XPD, FANCJ, RTEL1) implicated in genome maintenance and that may act as tumor suppressors [Parish et al 2006]. These helicases are crucial for DNA replication, repair, and sister chromatid cohesion. DDX11 is specifically involved in establishing sister chromatid cohesion during mitosis by promoting proper loading of the cohesin complex onto DNA [Parish et al 2006, Bharti et al 2014].

DDX11 is a superfamily 2 DNA helicase belonging to the iron-sulfur (Fe-S) cluster family of DNA helicase proteins [Hirota & Lahti 2000, Parish et al 2006]. Human Fe-S helicase family genes are implicated in genetic disorders including:

  • DDX11. DDX11-related cohesinopathy
  • ERCC2. Xeroderma pigmentosum (XP) group D, cerebrooculofacioskeletal syndrome 2, or trichothiodystrophy
  • RTEL1. Dyskeratosis congenita or Hoyeraal-Hreidarsson syndrome
  • BRIP1. Fanconi anemia complementation group J

DDX11 is an ATP-dependent DNA helicase [Hirota & Lahti 2000, Inoue et al 2007, Bharti et al 2014], which unwinds duplex DNA with a 5'-3' directionality and is essential for the correct assembly of cohesin onto DNA during mitosis [Parish et al 2006]. The DNA-unwinding activity of DDX11 is essential to its in vivo function. All analyzed DDX11 missense pathogenic variants whose amino acid substitutions are within the catalytic ATPase/helicase domain are either completely or near-completely devoid of helicase activity or are highly unstable in human cells [van der Lelij et al 2010, Capo-Chichi et al 2013, Alkhunaizi et al 2018]. Without this function, proper chromosomal cohesion is compromised, leading to chromosomal breakage and genome instability, the hallmark features underlying DDX11-related cohesinopathy syndrome. This syndrome is part of the broader group of cohesinopathies, which includes Cornelia de Lange and Roberts syndromes.

Mechanism of disease causation. Loss of function

Gene-specific laboratory considerations. Analysis of DDX11 is complicated by the presence of at least 16 highly homologous pseudogenes (e.g., DDX11L1, DDX11L2).

Table 6.

DDX11 Pathogenic Variants Referenced in This GeneReview

Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
NM_030653​.3 c.1763-1G>C--Ashkenazi Jewish founder variant [Rabin et al 2019]
NM_030653​.3
NP_085911​.2
c.2576T>Gp.Val859GlySaudi founder variant [Alkhunaizi et al 2018]

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

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Chapter Notes

Author History

Ebba Alkhunaizi, MD (2019-present)
Fowzan S Alkuraya, MD; Alfaisal University (2019-2025)
Robert M Brosh, Jr, PhD (2019-present)
David Chitayat, MD (2019-present)

Revision History

  • 5 June 2025 (sw) Comprehensive update posted live
  • 6 June 2019 (sw) Review posted live
  • 20 November 2018 (ea, dc) Original submission

References

Literature Cited

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  • Arroyo-Carrera I, Solo de Zaldivar-Tristancho M, Garcia Navas-Nunez VD, Ramajo-Polo A, Gutierrez-Agujetas M. [Warsaw breakage syndrome: an etiology for congenital microcephaly and sensorineural deafness]. Rev Neurol. 2023;76:111-5. [PMC free article: PMC10364041] [PubMed: 36703504]
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