CHROMOSOMAL IMBALANCES IN RUBINSTEIN-TAYBI PATIENTS NEGATIVE TO CREBBP MUTATIONAL TEST

Rubinstein-Taybi syndrome (RSTS, OMIM #180849) is a rare autosomal dominant congenital disorder characterized by postnatal growth retardation and psychomotor developmental delay, skeletal anomalies and specific facial dysmorphisms. RSTS is associated with chromosomal microdeletion or point mutations of CREBBP gene in 16p13.3 and mutations of EP300 gene in 22q13, observed in 56% and 3% of the tested patients respectively. Here we report the identification by a-CGH of duplications/deletions in 6 of 25 RSTS patients found negative to point mutations of CREBBP and to chromosomal rearrangements affecting CREBBP and EP300 regions. The imbalances are: i) a de novo 9Mb deletion in 2q24.3q31.1 involving the HOXD genes, ii) a 5,5 Mb duplication in 2q34q35 inherited by the healthy father, probably representing a private CNV, iii) a 500Kb duplication in 17q11.2 upstream the NF1 gene in a region delimited by NF1 REP-P1/P2 iv) a 1,2Mb deletion in 18q21.33q22.1 harbouring one gene, v) a 4,3Mb deletion in 2q22.3q23.1 involving five genes among which ZFHX1B, the gene mutated in Mowat-Wilson, vi) a 466Kb deletion in 7p21.1 containing TWIST1, a proposed candidate for RSTS. The parental origin, gene content and genomic characterization of the last four imbalances is in progress. Although the pathogenetic role is yet unproven in a few cases, this study shows a high fraction of chromosomal rearrangements in regions other than those of CREBBP/EP300 genes. In addition a-CGH is confirmed to be a suitable approach for diagnostic purposes and to highlight novel positional RSTS candidate genes.