Cryptic genomic imbalances in patients with de novo or familial apparently balanced translocations and abnormal phenotype

Abstract

BackgroundCarriers of apparently balanced translocations are usually phenotypically normal; however in about 6% of de novo cases, an abnormal phenotype is present. In the current study we investigated 12 patients, six de novo and six familial, with apparently balanced translocations and mental retardation and/or congenital malformations by applying 1 Mb resolution array-CGH. In all de novo cases, only the patient was a carrier of the translocation and had abnormal phenotype. In five out of the six familial cases, the phenotype of the patient was abnormal, although the karyotype appeared identical to other phenotypically normal carriers of the family. In the sixth familial case, all carriers of the translocations had an abnormal phenotype.ResultsChromosomal and FISH analyses suggested that the rearrangements were "truly balanced" in all patients. However, array-CGH, revealed cryptic imbalances in three cases (3/12, 25%), two de novo (2/12, 33.3%) and one familial (1/12, 16.6%). The nature and type of abnormalities differed among the cases. In the first case, what was identified as a de novo t(9;15)(q31;q26.1), a complex rearrangement was revealed involving a ~6.1 Mb duplication on the long arm of chromosome 9, an ~10 Mb deletion and an inversion both on the long arm of chromosome 15. These imbalances were located near the translocation breakpoints. In the second case of a de novo t(4;9)(q25;q21.2), an ~6.6 Mb deletion was identified on the short arm of chromosome 7 which is unrelated to the translocation. In the third case, of a familial, t(4;7)(q13.3;p15.3), two deletions of ~4.3 Mb and ~2.3 Mb were found, each at one of the two translocation breakpoints. In the remaining cases the translocations appeared balanced at 1 Mb resolution.ConclusionThis study investigated both de novo and familial apparently balanced translocations unlike other relatively large studies which are mainly focused on de novo cases. This study provides additional evidence that cryptic genomic imbalances are common in patients with abnormal phenotype and "apparently balanced" translocations not only in de novo but can also occur in familial cases. The use of microarrays with higher resolution such as oligo-arrays may reveal that the frequency of cryptic genomic imbalances among these patients is higher.

Chromosomal disorders and male infertility

“…aCGH is already widely used for the cytogenetic analysis of prenatal and postnatal samples [104][105][106][107] as it is rapid, cost-effective and allows chromosomal regions to be screened at high resolution. Several types of aCGH platform are available for the purposes of aneuploidy screening.…”

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

“…Interestingly, by empirical studies, ;6% of de novo apparently balanced translocations are associated with clinical abnormalities (Warburton 1991). Recently, it has been shown by molecular analyses (e.g., array comparative genomic hybridization) that up to 40% of the apparently balanced reciprocal chromosome translocations in patients with an abnormal phenotype are accompanied by a chromosome imbalance, either at the translocation breakpoints or elsewhere in the genome (Gribble et al 2005;De Gregori et al 2007;Sismani et al 2008). Little is known, however, about the mechanisms or genomic sequences involved in the formation of non-neoplastic reciprocal translocations (Abeysinghe et al 2003;Higgins et al 2008).…”

Hydroxyurea and Anagrelide Combination Therapy in Patients with Chronic Myeloproliferative Diseases Resistant or Intolerant to Monotherapy

“…The combination was also effective in regard to vascular complications, with no official thrombotic event apart from erythromelalgia in an ET patient and 1 case of minor hemorrhage in a patient also receiving clopidogrel. The latter maybe associated with a synergistic functional PLT inhibition by AG and clopidogrel [10]. Given the superiority of HU in preventing arterial events and of AG in venous thrombosis as shown in the PT-1 trial [10], a complementary effect of these drugs could be beneficial.…”