CLINICAL IMPACT OF PROXIMAL AUTOSOMAL IMBALANCES
Hamid AB, Weise A, Voigt M, Bucksch M, Kosyakova N, Liehr T,* Klein E
*Corresponding Author: Dr. Thomas Liehr, Universitätsklinikum Jena, Institut für Humangenetik, Kollegiengasse 10, D-07743 Jena, Germany; Tel.: +49-3641-935533; Fax. ++49-3641-935582; E-mail: i8lith@mti.uni-jena.de
page: 15

MATERIALS AND METHODS

This study is based on the data summarized on the sSMC-homepage [6]. All raw data is freely available and can be followed down to each individual case. The data used for the present study is summarized in Tables 1 through 4. Proximal Chromosomal Imbalances Without Clinical Consequences. The available in detail characterized sSMC cases [6] were studied by various approaches. In the majority of cases, the sSMC were characterized exclusively by molecular cytogenetics and the breakpoints are given as cytobands without molecular assessment of the exact breakpoint. In addition, there are already numerous sSMC cases characterized by well-defined locus-specific probes used in fluorescence in situ hybridization (FISH) and/or by aCGH [6]. In Table 3, the presently characterized C-UBCA are summarized. Overall, it could be shown that at least 96.8 Mb of the proximal chromosomal regions are tolerated as triplicates or more (Table 3). While for proximal 6q there is neither molecular nor cytogenetic hint for any dosage independent C-UBCA, in all other proximal autosomal parts at least cytogenetic evidence for C-UBCA in healthy individuals is there. Except for proximal parts of 1q, 6p, 6q and 13q, there are molecular hints on C-UBCA for every chromosome arm, being at least between 0.07 and 10.23 Mb in size. According to cytogenetics, no less than 16 of the 39 autosomal proximal non dosage sensitive regions (= C-UBCA) are larger than already proven by aCGH, i.e., 2p, 3p, 3q, 6p, 8p, 8q, 9p, 9q, 10p, 10q, 11p, 12p, 19p, 19q, 20p and 22q (Table 3). Twenty-four of the 38 informative proximal autosomal regions are based on mosaic sSMC cases. Thus, the data summarized in Table 3 is still to be considered as preliminary in those cases, even though in >99.0% of sSMC cases, mosaicism detected in peripheral blood plays a minor role for the clinical outcome [22]. Mosaicism may play a role for the phenotype if its rates are variant in different tissues of the body [23]. The C-UBCA regions 1p, 3p, 5p, 10p, 10q, 11p, 13q, 14q, 15q, 16p, 16q, 18p, 21q and 22q were reported in non mosaic cases. The remaining regions await such proof. Another issue to be reflected is the copy number of a C-UBCA tolerated by the human genome. At least, for 15 C-UBCA low mosaics (maximum 20.0%) of cells having four (or in one case of 20q up to six) copies of the corresponding regions are tolerated. The C-UBCA of chromosomes 13q, 14q and 15q can be present in four copies in normal carriers in 100.0% of the studied cells. For 15q, even six copies are possible (Table 3). Autosomal Proximal Imbalances Leading to Clinical Consequences. In case an sSMC or an intrachromo- somal duplication is larger than the critical region for harmless sSMC, as summarized Table 3, a variety of clinical problems can be the consequence for the sSMC carrier. Besides well-known syndromes such as isochromosome-12p (Pallister-Killian syndrome) [24], -15q [25], -18p [26] or -22q (cat-eyesyndrome) [27], a variety of symptoms can be associated with an sSMC-induced imbalance [3,6]. In most cases the correlated symptoms are rather non specific. However, first potentially specific symptom combinations for nine corresponding imbalances are summarized in Table 4. In future, it should be possible for at least some of these proximal autosomal imbalances to define new, possibly even clinically recognizable, syndromes [3].



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