title: Novel SMARCAL1 bi-allelic mutations associated with a chromosomal breakage phenotype in a severe SIOD patient.
abstract: OBJECTIVE
  Chromosomal instability syndromes include a group of rare diseases characterized by defective DNA-damage-response and increased risk of chromosomal breakage. Patients display defects in the recognition and/or repair of DNA damage, with a subsequent high rate of malignancies and abnormal gene rearrangements. Other clinical manifestations, such as immunodeficiency, neurodevelopmental delay and skeletal abnormalities, are present in some of these syndromes. We studied a patient with profound T-lymphocyte defect, neurodevelopmental delay, facial dysmorphism, nephrotic syndrome and spondyloepiphyseal bone dysplasia typical of SIOD.
  
  
  METHODS
  Karyotype and chromosome fragility assays on patients' peripheral blood mononuclear cells showed an abnormal rate of spontaneous breaks. Cell cycle analysis of patient's fibroblasts following replication stress induced by hydroxyhurea revealed a delay in their release from S-phase to G2. When using higher concentrations of hydroxyhurea no patient fibroblast colonies could survive, compared with control fibroblasts. Whole-exome sequencing revealed novel compound heterozygote mutations in SMARCAL1 gene, resulting in putative frame shifts of encoded SMARCAL1 from each allele and no detected protein in patient's cells. The patient's youngest brother was found to have similar manifestations of SIOD but of less severity, including short stature, facial dysmorphism and typical osseous dysplasia, but no clinical findings suggestive of immunodeficiency and no chromosomal fragility. Similar to his sister, the brother carries both bi-allelic mutations in SMARCAL1 gene.
  
  
  CONCLUSIONS
  We present here the first evidence of intrinsic chromosomal instability in a severe SMARCAL1-deficient patient with a clinical picture of SIOD. Our results are consistent with the recently outlined role of SMARCAL1 protein in DNA damage response.
authors.affiliation: Cancer Research Center, Chaim Sheba Medical Center, Tel Hashomer, 52621, Israel, amos.simon@sheba.health.gov.il.
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Atar
authors.initials: A
authors.lastname: Lev
authors.forename: Marta
authors.initials: M
authors.lastname: Jeison
authors.forename: Zvi U
authors.initials: ZU
authors.lastname: Borochowitz
authors.forename: David
authors.initials: D
authors.lastname: Korn
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lerenthal
authors.forename: Raz
authors.initials: R
authors.lastname: Somech
mesh_terms: D000483:Alleles; D001161:Arteriosclerosis / Q000175:diagnosis* / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002675:Child, Preschool; D043171:Chromosomal Instability; D002871:Chromosome Banding; D019457:Chromosome Breakage; D004265:DNA Helicases / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D006579:Heterozygote; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000175:diagnosis* / Q000235:genetics*; D016130:Immunophenotyping; D007223:Infant; D008214:Lymphocytes / Q000378:metabolism; D008297:Male; D009154:Mutation; D009404:Nephrotic Syndrome / Q000175:diagnosis* / Q000235:genetics*; D016366:Open Reading Frames; D010009:Osteochondrodysplasias / Q000175:diagnosis* / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism / Q000175:diagnosis* / Q000235:genetics*; D022821:RNA Splice Sites
chemical_list: D022821:RNA Splice Sites; C412482:SMARCAL1 protein, human; D004265:DNA Helicases