Warsaw breakage syndrome (WABS) is a rare disease caused by mutations in the DDX11 gene. It is characterized by severe growth restriction, microcephaly, and sensorineural hearing loss, and reports of coexisting epilepsy are even rarer. There are no studies on the focused synthesis of epilepsy phenotypes in WABS. A clinical review is conducted for a patient diagnosed with WABS. And a comprehensive search is performed using PubMed, Web of Science, and Scopus. We select only papers that report patients with WABS and epilepsy. We present a boy exhibiting the core manifestations of this syndrome. In addition to growth restriction, microcephaly, and sensorineural hearing loss, he has experienced recurrent epileptic seizures since 7 months of age. The child showed resistance to multiple antiepileptic drugs, with seizure types progressing from focal to epileptic spasms. Whole-exome sequencing identified two variants in the patient's DDX11 gene: c.2120delT (p.F707Sfs*60) and c.1949-3C>T (splicing). A literature review identified a total of 7 previously reported children with WABS complicated by epilepsy, and we collected and summarized their clinical and genetic information. We report a child with WABS whose main symptom was epilepsy. This case expands the known mutation spectrum of WABS and provides a comprehensive summary of clinical and genetic data for WABS patients presenting with epilepsy.

Currently, exome and genome sequencing achieve a diagnostic rate of 30%-50% for rare genetic diseases. With multi-modal technologies profiling the genome, transcriptome, and epigenome, interrogation of genomic elements outside of protein-coding regions shows potential to improve this as demonstrated herein. Siblings with sensorineural hearing loss, microcephaly, intellectual impairment, and growth restriction were seen in consultation. Following extensive clinical testing, long-read whole genome and cDNA-based transcriptome sequencing on the Oxford Nanopore platform identified a homozygous 1.6 kb deletion of the 5' UTR and promoter region of DDX11, a gene associated with Warsaw breakage syndrome. The deletion included the hypomethylated CpG island regulating DDX11, led to a loss of expression of DDX11 mRNA and protein, and resulted in the characteristic "railroad chromosome." Identifying a causal variant for this family required expanding the search space for genomic variants beyond protein-coding regions, and multi-modal data integration enabled a more holistic approach to variant prioritization and classification prior to pursuing targeted protein and functional assays. This multi-modal genome-wide approach heralds promise for patients on the diagnostic odyssey and who have exhausted standard of care testing. 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. The diagnosis of DDX11-related cohesinopathy is established in a proband with biallelic pathogenic variants in DDX11 identified by molecular genetic testing. 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. 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.

DNA double strand break repair (DSBR) represents a fundamental process required to maintain genome stability and prevent the onset of disease. Whilst cell cycle phase and the chromatin context largely dictate which repair pathway is utilised to restore damaged DNA, it has been recently shown that nuclear actin filaments play a major role in clustering DNA breaks to facilitate DSBR by homologous recombination (HR). However, the mechanism with which nuclear actin and the different actin nucleating factors regulate HR is unclear. Interestingly, patients with biallelic mutations in the actin nucleating factor DIAPH1 exhibit a striking overlap of clinical features with the HR deficiency disorders, Nijmegen Breakage Syndrome (NBS) and Warsaw Breakage Syndrome (WABS). This suggests that DIAPH1 may play a role in regulating HR and that some of the clinical deficits associated with DIAPH1 mutations may be caused by an underlying DSBR defect. In keeping with this clinical similarity, we demonstrate that cells from DIAL (DIAPH1 Loss-of-function) Syndrome patients display an HR repair defect comparable to loss of NBS1. Moreover, we show that this DSBR defect is also observed in a subset of patients with Baraitser-Winter Cerebrofrontofacial (BWCFF) syndrome associated with mutations in ACTG1 (γ-actin) but not ACTB (β-actin). Lastly, we demonstrate that DIAPH1 and γ-actin promote HR-dependent repair by facilitating the relocalisation of the MRE11/RAD50/NBS1 complex to sites of DNA breaks to initiate end-resection. Taken together, these data provide a mechanistic explanation for the overlapping clinical symptoms exhibited by patients with DIAL syndrome, BWCFF syndrome and NBS.

DDX11 is a DNA helicase involved in critical cellular functions, including DNA replication/repair/recombination as well as sister chromatid cohesion establishment. Bi-allelic mutations of DDX11 lead to Warsaw breakage syndrome (WABS), a rare genome instability disorder marked by significant prenatal and postnatal growth restriction, microcephaly, intellectual disability, and sensorineural hearing loss. The molecular mechanisms underlying WABS remain largely unclear. In this study, we uncover a novel role of DDX11 in regulating the macroautophagic/autophagic pathway. Specifically, we demonstrate that knockout of DDX11 in RPE-1 cells hinders the progression of autophagy. DDX11 depletion significantly reduces the conversion of MAP1LC3/LC3 (microtubule associated protein 1 light chain 3), suggesting a defect in autophagosome biogenesis. This is supported by imaging analysis with a LC3 reporter fused in tandem with the red and green fluorescent proteins (mRFP-GFP-LC3), which reveals fewer autophagosomes and autolysosomes in DDX11-knockout cells. Moreover, the defect in autophagosome biogenesis, observed in DDX11-depleted cells, is linked to an upstream impairment of the ATG16L1-precursor trafficking and maturation, a step critical to achieve the LC3 lipidation. Consistent with this, DDX11-lacking cells exhibit a diminished capacity to clear aggregates of a mutant HTT (huntingtin) N-terminal fragment fused to the green fluorescent protein (HTTQ74-GFP), an autophagy substrate. Finally, we demonstrate the occurrence of a functional interplay between DDX11 and SQSTM1, an autophagy cargo receptor protein, in supporting LC3 modification during autophagosome biogenesis. Our findings highlight a novel unprecedented function of DDX11 in the autophagy process with important implications for our understanding of WABS etiology.Abbreviations: ATG autophagy related; BAF A1 bafilomycin A1; CTRL control; DDX11 DEAD/H-box; helicase 11; HF1 healthy donor fibroblasts; HTT huntingtin; KO knockout; MAP1LC3/LC3; microtubule associated protein 1 light chain 3; PLA proximity ligation assay; RPE-1 retinal; pigment epithelial cell line 1; TUBA α-TUBULIN; UBA ubiquitin binding domain; WABS Warsaw breakage syndrome.

Warsaw Breakage Syndrome (WABS) is a rare autosomal recessive cohesinopathy characterized by growth retardation and congenital anomalies. This report aims to highlight the prenatal diagnosis of WABS through ultrasound findings and genetic testing. We report a case of prenatal diagnosis of WABS in a 24-week gestation fetus exhibiting microcephaly, delayed sulcation, short corpus callosum, cerebellar vermis hypoplasia and intrahepatic portal-systemic shunts. The couple had a history of a prior pregnancy termination due to severe intrauterine growth restriction and cerebral malformations. Whole exome sequencing revealed compound heterozygous pathogenic variants [NM_030653.4:c.1403dupT, p.(Ser469Valfs*32) and c.1672C>T, p.(Arg558*)] in the DDX11 gene, consistent with WABS. The same pathogenic variants were identified in the prior terminated fetus upon subsequent analysis. Postmortem examination of the proband confirmed the prenatal ultrasound findings. This case expands the understanding of the prenatal phenotypic spectrum of WABS by identifying specific cerebral and extracerebral anomalies associated with pathogenic variants in the DDX11 gene. Incorporating advanced genetic diagnostics like whole exome sequencing into prenatal care provides valuable information for genetic counseling and management of rare genetic disorders.