DDX11 and Warsaw Breakage Syndrome

This summary integrates extensive clinical and experimental evidence supporting the association between DDX11 (HGNC:2736) and Warsaw breakage syndrome (MONDO:0013252). Multiple independent studies have identified bi-allelic pathogenic variants in DDX11 among affected individuals presenting with diverse and severe congenital anomalies including intellectual disability, abnormal skin pigmentation, microcephaly, and facial dysmorphism (PMID:23033317, PMID:25701697). The disorder is inherited in an autosomal recessive pattern with disease-segregating variants confirmed in consanguineous families and compound heterozygous cases. This evidence underscores a robust genetic basis and clinical presentation that aligns with the described phenotype of Warsaw breakage syndrome.

Genetic evidence from case reports and multi‐patient studies demonstrates a broad variant spectrum in DDX11. Reported variant classes include missense, splice, and frameshift changes. For instance, the novel variant c.788G>A (p.Arg263Gln) was identified in three affected siblings in a Lebanese consanguineous family, providing clear segregation data (PMID:23033317). Additional studies have reported compound heterozygous events in unrelated families that recapitulate the key phenotypic features of the syndrome, such as pre‑ and postnatal growth failure, sensorineural hearing impairment, and cutaneous manifestations (PMID:28960803, PMID:30924321).

In-depth pedigree analyses and segregation studies across multiple families provide compelling support for an autosomal recessive inheritance model. Affected siblings and additional segregating relatives further validate the genetic link between DDX11 variants and the disease phenotype. The aggregation of data from several independent cohorts, including studies of diverse ethnic origins, strengthens the association and suggests that recurrent or founder variants contribute to the observed clinical spectrum (PMID:31287223).

Experimental and functional studies have been instrumental in elucidating the pathogenic mechanism underlying Warsaw breakage syndrome. Biochemical assays have shown that the p.Arg263Gln mutation disrupts DDX11 helicase activity by impairing both DNA binding and ATP hydrolysis (PMID:22102414). Supporting evidence from animal models, including mouse embryos exhibiting early developmental arrest and defects in sister chromatid cohesion, further corroborates the notion that loss of DDX11 function is central to the disease process (PMID:22678773).

Integrative analyses confirm that genetic and functional data converge to support a strong gene-disease association. The combination of clearly segregating pathogenic variants in multiple affected families and convergent functional experiments demonstrating impaired helicase activity meets the criteria for a strong ClinGen classification. Although additional evidence exists beyond the minimal threshold for scoring, the collective data provide an unambiguous framework for diagnostic decision-making and therapeutic considerations.

Key take‑home: Rigorous genetic and experimental evidence firmly supports the clinical utility of testing for DDX11 variants in individuals with features of Warsaw breakage syndrome, facilitating accurate diagnosis and risk assessment in clinical and commercial settings.

References

• Human Mutation • 2013 • Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome PMID:23033317
• European Journal of Medical Genetics • 2015 • Warsaw Breakage Syndrome--A further report, emphasising cutaneous findings PMID:25701697
• American Journal of Medical Genetics. Part A • 2017 • Clinical Report: Warsaw Breakage Syndrome with small radii and fibulae PMID:28960803
• Prenatal Diagnosis • 2024 • Prenatal Diagnosis of Warsaw Breakage Syndrome: Fetal Compound Heterozygous Variants in the DDX11 Gene Associated With Growth Restriction, Cerebral, and Extra-Cerebral Malformations PMID:39428552
• Molecular Genetics & Genomic Medicine • 2019 • Two further patients with Warsaw breakage syndrome. Is a mild phenotype possible? PMID:30924321
• Nature Communications • 2020 • Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion PMID:32855419
• The Journal of Biological Chemistry • 2012 • Biochemical characterization of Warsaw breakage syndrome helicase PMID:22102414
• Developmental Dynamics • 2012 • The ENU-induced cetus mutation reveals an essential role of the DNA helicase DDX11 for mesoderm development during early mouse embryogenesis PMID:22678773
• PLOS One • 2015 • The Q Motif Is Involved in DNA Binding but Not ATP Binding in ChlR1 Helicase PMID:26474416

Evidence Based Scoring (AI generated)