title: A novel frameshift mutation in BLM gene associated with high sister chromatid exchanges (SCE) in heterozygous family members.
abstract: The Bloom syndrome (BS) is an autosomic recessive disorder comprising a wide range of abnormalities, including stunted growth, immunodeficiency, sun sensitivity and increased frequency of various types of cancer. Bloom syndrome cells display a high level of genetic instability, including a 10-fold increase in the sister chromatid exchanges (SCE) level. Bloom syndrome arises through mutations in both alleles of the BLM gene, which was identified as a member of the RecQ helicase family. In this study, we screened a Tunisian family with three BS patients. Cytogenetic analysis showed several chromosomal aberrations, and an approximately 14-fold elevated SCE frequency in BS cells. A significant increase in SCE frequency was observed in some family members but not reaching the BS patients values, leading to suggest that this could be due to the heterozygous profile. Microsatellite genotyping using four fluorescent dye-labeled microsatellite markers revealed evidence of linkage to BLM locus and the healthy members, sharing higher SCE frequency, showed heterozygous haplotypes as expected. Additionally, the direct BLM gene sequencing identified a novel homozygous frameshift mutation c.3617-3619delAA (p.K1207fsX9) in BS patients and a heterozygous BLM mutation in the family members with higher SCE frequency. Our findings suggest that this latter mutation likely leads to a reduced BLM activity explaining the homologous recombination repair defect and, therefore, the increase in SCE. Based on the present data, the screening of this mutation could contribute to the rapid diagnosis of BS. The genetic confirmation of the mutation in BLM gene provides crucial information for genetic counseling and prenatal diagnosis.
authors.affiliation: Laboratory of Human Molecular Genetics, Faculty of Medicine, University of Sfax, Av. Majida Boulila, 3029, Sfax, Tunisia, ghada.bsalah@gmail.com.
authors.forename: Ghada
authors.initials: G
authors.lastname: Ben Salah
authors.forename: Ikhlas
authors.initials: I
authors.lastname: Hadj Salem
authors.forename: Abderrahmen
authors.initials: A
authors.lastname: Masmoudi
authors.forename: Fakhri
authors.initials: F
authors.lastname: Kallabi
authors.forename: Hamida
authors.initials: H
authors.lastname: Turki
authors.forename: Faiza
authors.initials: F
authors.lastname: Fakhfakh
authors.forename: Hamadi
authors.initials: H
authors.lastname: Ayadi
authors.forename: Hassen
authors.initials: H
authors.lastname: Kamoun
mesh_terms: D001483:Base Sequence; D001816:Bloom Syndrome / Q000235:genetics*; D019295:Computational Biology; D020732:Cytogenetic Analysis; D004252:DNA Mutational Analysis; D016368:Frameshift Mutation / Q000235:genetics*; D040461:Gene Components; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D010375:Pedigree; D053484:RecQ Helicases / Q000235:genetics*; D012854:Sister Chromatid Exchange / Q000235:genetics*; D014416:Tunisia
chemical_list: C097151:Bloom syndrome protein; D053484:RecQ Helicases