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Introducción: El síndrome de rotura de Varsovia es una alteración genética muy poco frecuente originada por variantes patógenas bialélicas en el gen DDX11, implicado en la cohesión de las cromátidas hermanas, que pertenece al grupo de las cohesinopatías. Clínicamente se caracteriza por retraso del crecimiento, microcefalia y sordera neurosensorial, con otras manifestaciones menos frecuentes: dismorfia facial, anomalías esqueléticas, cardíacas, cutáneas y genitourinarias. Caso clínico: Presentamos a un varón con las manifestaciones cardinales del síndrome: bajo peso en el nacimiento, microcefalia congénita grave y sordera neurosensorial con agenesia de los nervios cocleares. También presenta cardiopatía, hipospadias, criptorquidia, anomalía cutánea y pies planos. En el exoma se han identificado dos variantes en heterocigosis probablemente patógenas en el gen DDX11, c.1403dup; p.(Ser469Valfs*32) y c.2371C>T; p.(Arg791Trp), heredadas cada una de un progenitor. Conclusión: Revisamos a los 23 pacientes descritos con el síndrome en la bibliografía, tanto desde el punto de vista clínico como desde el genético. Analizamos el significado etiopatógeno de las variantes de nuestro caso basándonos en los datos moleculares y las funciones celulares de DDX11 de los estudios publicados. Debido al solapamiento clínico con los síndromes con rotura cromosómica y las cohesinopatías, debemos realizar el diagnóstico diferencial con estas entidades, fundamentalmente la anemia de Fanconi, el síndrome de rotura de Nijmegen, el síndrome de Cornelia de Lange y el síndrome de Roberts. En la práctica clínica, debemos sospechar este síndrome en el período neonatal en un paciente con retraso del crecimiento intrauterino, microcefalia grave y sordera neurosensorial.(AU)

Introduction: Warsaw breakage syndrome is a very rare genetic disorder due to biallelic pathogenic variants in DDX11 gene, with a role in the sister chromatid cohesion process, and classified in the cohesinophaties group. It is characterized by the clinical triad of growth restriction, microcephaly and sensorineural deafness. Additional, but less frequent features, are facial dysmorphism, and skeletal, heart, skin and genitourinary anomalies. Case report: We report a boy with the cardinal features of the syndrome: prenatal growth restriction, severe congenital microcephaly, and sensorineural deafness with cochlear nerves agenesis. He also has a cardiac anomaly, hypospadias, cryptorchidism, skin abnormality, and pes planus. The exome yielded two heterozygous likely pathogenic variants in the DDX11 gene, c.1403dup; p.(Ser469Valfs*32) and c.2371C>T; p.(Arg791Trp), inherited in trans from the parents. Conclusion: We review the clinical and genetic data of the 23 reported cases with the syndrome in the literature and analyze the etiopathogenic interpretation of our case variants based on the molecular and cellular functions of DDX11 described. Due to the clinical overlap with the chromosomal breakage syndromes and cohesinopathies we must make the differential diagnosis with these entities, overall, with Fanconi anemia, Nijmegen breakage syndrome, Cornelia de Lange syndrome and Roberts syndrome. In clinical practice we must think in Warsaw breakage syndrome in the neonatal period in a patient with intrauterine growth restriction, severe microcephaly, and sensorineural deafness.(AU)

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Warsaw breakage syndrome (WABS) is a very rare recessive hereditary disease caused by mutations in the gene coding for the DNA helicase DDX11, involved in genome stability maintenance and sister cohesion establishment. Typical clinical features observed in WABS patients include growth retardation, facial dysmorphia, microcephaly, hearing loss due to cochlear malformations and, at cytological level, sister chromatid cohesion defects. Molecular bases of WABS have not yet been elucidated, due to lack of disease animal model systems and limited knowledge of the DDX11 physiological functions. However, WABS is considered to belong to the group of cohesinopathies, genetic disorders due to mutations of subunits or regulators of cohesin, the protein complex responsible for tethering sister chromatids from the time of their synthesis till they separate in mitosis. Recent evidences suggest that cohesin and its regulators have additional key roles in chromatin organization by promoting the formation of chromatin loops. This "non-canonical" function of cohesin is expected to impact gene transcription during cell differentiation and embryonic development and its dis-regulation, caused by mutation/loss of genes encoding cohesin subunits or regulators, could originate the developmental defects observed in cohesinopathies. Ethiopathogenesis of WABS is discussed in line with these recent findings and evidence of a possible role of DDX11 as a cohesin regulator.

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Warsaw breakage syndrome (WABS), caused by bi-allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre- and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron-sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763-1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763-1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.

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BACKGROUND: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. METHODS: Mutational screening and functional analyses (protein expression and 3D-modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. RESULTS: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three-dimensional modeling, as well as expression analysis. CONCLUSION: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability.

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DDX11/ChlR1 (Chl1 in yeast) is a DNA helicase involved in sister chromatid cohesion and in DNA repair pathways. The protein belongs to the family of the iron⁻sulphur cluster containing DNA helicases, whose deficiencies have been linked to a number of diseases affecting genome stability. Mutations of human DDX11 are indeed associated with the rare genetic disorder named Warsaw breakage syndrome, showing both chromosomal breakages and chromatid cohesion defects. Moreover, growing evidence of a potential role in oncogenesis further emphasizes the clinical relevance of DDX11. Here, we illustrate the biochemical and structural features of DDX11 and how it cooperates with multiple protein partners in the cell, acting at the interface of DNA replication/repair/recombination and sister chromatid cohesion to preserve genome stability.

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Warsaw breakage syndrome (WBS) is a recently recognized DDX11-related rare cohesinopathy, characterized by severe prenatal and postnatal growth restriction, microcephaly, developmental delay, cochlear anomalies, and sensorineural hearing loss. Only seven cases have been reported in the English literature, and thus the information on the phenotype and genotype of this interesting condition is limited. We provide clinical and molecular information on five additional unrelated patients carrying novel bi-allelic variants in the DDX11 gene, identified via whole exome sequencing. One of the variants was found to be a novel Saudi founder variant. All identified variants were classified as pathogenic or likely pathogenic except for one that was initially classified as a variant of unknown significance (VOUS) (p.Arg378Pro). Functional characterization of this VOUS using heterologous expression of wild type and mutant DDX11 revealed a marked effect on protein stability, thus confirming pathogenicity of this variant. The phenotypic data of the seven WBS reported patients were compared to our patients for further phenotypic delineation. Although all the reported patients had cochlear hypoplasia, one patient also had posterior labyrinthine anomaly. We conclude that while the cardinal clinical features in WBS (microcephaly, growth retardation, and cochlear anomalies) are almost universally present, the breakage phenotype is highly variable and can be absent in some cases. This report further expands the knowledge of the phenotypic and molecular features of WBS.

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We present two new cases of Warsaw Breakage Syndrome (WABS), an autosomal recessive cohesinopathy, in sisters aged 13 and 11 years who both had compound heterozygous mutations in DDX11. After exclusion of Fanconi anemia, Bloom syndrome and Nijmegen breakage syndrome, whole exome sequencing revealed two novel variants-c.1523T>G, predicting (p.Leu508Arg) and c.1949-1G>A (IVS19-1G>A), that were confirmed with Sanger sequencing in both affected individuals. DDX11 encodes an iron-sulfur-containing DNA helicase, and mutations in this gene have been reported in the five WABS cases previously identified to date. The sisters reported here display the distinguishing clinical features of WABS: pre- and post-natal growth restriction, microcephaly, intellectual disability, sensorineural hearing loss with cochlear abnormalities, and facial dysmorphic features. In addition, our cases had early menarche at 8 and 10 years of age, bilateral small thumbs, and the younger, more severely affected sister had small fibulae. These findings broaden the WABS phenotype and the limb malformations demonstrate further clinical overlap with Fanconi anemia and other cohesinopathies, such as Roberts Syndrome.

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Cohesin is a multiprotein complex involved in many DNA-related processes such as proper chromosome segregation, replication, transcription, and repair. Mutations in cohesin gene pathways are responsible for human diseases, collectively referred to as cohesinopathies. In addition, both cohesin gene expression dysregulation and mutations have been identified in cancer. Cohesinopathy cells are characterized by genome instability (GIN) visualized by a constellation of markers such as chromosome aneuploidies, chromosome aberrations, precocious sister chromatid separation, premature centromere separation, micronuclei formation, and sensitivity to genotoxic drugs. The emerging picture suggests that GIN observed in cohesinopathies may result from the synergistic effects of the multiple cohesin dysfunctions. © 2016 Wiley Periodicals, Inc.

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We report a new case of Warsaw Breakage syndrome (WABS) with 2 confirmed mutations in DDX11. Like the previous reported cases [Capo-Chichi et al., 2012; Van der Lelij et al., 2010], there was evidence of pre- and postnatal growth retardation, severe microcephaly, intellectual disability and facial dysmorphism. The patient had sensorineural hearing loss with evidence of bilateral hypoplastic cochleas on imaging, another feature which has been reported in the previous cases of WABS. In our case the patient exhibited a chronic rash of livedo reticularis with telangiectasia on her legs. Abnormally pigmented lesions and cutis mamorata were reported in the original WABS case.

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The encouraging response rates of BRCA1- and BRCA2-mutated cancers toward PARP inhibitors make it worthwhile to identify other potential determinants of PARP inhibitor responsiveness. Since the Fanconi anemia (FA) pathway coordinates several DNA repair pathways, including homologous recombination in which BRCA1 and BRCA2 play important roles, we investigated whether this pathway harbors other predictors of PARP inhibitor sensitivity. Lymphoblastoid cell lines derived from individuals with FA or clinically related syndromes, such as Warsaw breakage syndrome, were tested for PARP inhibitor sensitivity. Remarkably, we found a strong variability in PARP inhibitor sensitivity among different FANCD1/BRCA2-deficient lymphoblasts, suggesting that PARP inhibitor response depends on the type of FANCD1/BRCA2 mutation. We identified the DNA helicases FANCM and DDX11 as determinants of PARP inhibitor response. These results may extend the utility of PARP inhibition as effective anticancer treatment.

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The ChlR1 DNA helicase is mutated in Warsaw breakage syndrome characterized by developmental anomalies, chromosomal breakage, and sister chromatid cohesion defects. However, the mechanism by which ChlR1 preserves genomic integrity is largely unknown. Here, we describe the roles of ChlR1 in DNA replication recovery. We show that ChlR1 depletion renders human cells highly sensitive to cisplatin; an interstrand-crosslinking agent that causes stalled replication forks. ChlR1 depletion also causes accumulation of DNA damage in response to cisplatin, leading to a significant delay in resolution of DNA damage. We also report that ChlR1-depleted cells display defects in the repair of double-strand breaks induced by the I-PpoI endonuclease and bleomycin. Furthermore, we demonstrate that ChlR1-depeleted cells show significant delays in replication recovery after cisplatin treatment. Taken together, our results indicate that ChlR1 plays an important role in efficient DNA repair during DNA replication, which may facilitate efficient establishment of sister chromatid cohesion.

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