Balkan Journal of Medical Genetics

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

INTRODUCTION

Autosomal Proximal Chromosome Imbalances. The finding of unbalanced chromosomal abnormalities (UBCA) was recently reviewed and summarized from a total of 200 families. The UBCA usually involve several megabases of DNA. Carriers of such UBCA are ascertained due to adverse reproductive effects or dysmorphic and/or mentally retarded offspring; the carriers themselves have an otherwise normal phenotype. Unbalanced chromosomal abnormalities have been reported for more than 50 euchromatic regions of almost all human autosomes [1,2]. Unbalanced chromosomal abnormalities leading to gain of genetic relevant material within the autosomal centromere-near region were not comprehensively followed in the above mentioned studies [1,2]. Such centro-mere-near, i.e., proximal chromosomal imbalances (C-UBCA), can be induced by small supernumerary marker chromosomes (sSMCs) [3,4] and also by intrachromo-somal duplications [4]. While the latter are rare events and no reliable data on their frequency is available, sSMCs are present in 0.043% of human beings [5]. With a given population size of 7 × 109 individuals, 3 × 106 sSMC carriers are presently alive. As ~2/3 of these do not show any symptoms, ~2 × 106 do not even know of their condition. Euchromatin is present in ~36.0% of those sSMC cases that do not lead to any clinical symptoms (Table 1) [6]. N.B.: sSMC, irrespective of origin and genetic constitution may cause fertility problems, especially in males [7]. Thus, infertility was not considered as an ‘abnormal phenotype’ in this study. Even though partial trisomy is the most frequent imbalance induced by sSMC, tetra- or even hexasomy of proximal euchromatin may be present in clinically healthy individuals [6]. Here we present the latest known proximal, centromere-near regions and their minimal molecular borders. The corresponding index cases were previously published and are summarized on the sSMC homepage [6]. This study intends to give a review on the clinical impact of proximal autosomal imbalances. A special focus is hereby laid on gain of copy numbers. For this, the following steps were necessary: i) define the pericentric regions that can be present as additional copy(ies) without causing any clinical phenotype. ii) After the definition of such copy number insensitive regions, in a second step, proximal autosomal regions including genes potentially sensitive to copy numbers can be defined. iii) Such copy number sensitive regions can be correlated with specific, typical symptoms; the latter already being possible for nine centromere-near regions in this study and there will be more in the future. What Can be Learned From Cases With Chromosome Imbalances? It was nicely summarized back in 1993 [8] that structural autosomal imbalances may lead in ‘typical cases’ to syndromes with a complex of minor anomalies and/or congenital malformations. The latter ‘suggests the importance of gene interaction in determining the phe-notypic picture of autosomal imbalance syndromes’ [8]. Duplication- related syndromes are much more frequent than deletion-related ones, and thus, it is common sense that in general, duplications of several Mb in size are better tolerated by the human genome than deletions of the same size. This has also recently been confirmed on the level of micro-duplications and -deletions [9]. Overall, chromosomal imbalances can point towards dosage sensitive genes being responsible for specific syndromes or clinical features. A good example is the dosage sensitive peripheral myelin protein 22 (PMP22) gene in 17p11.2: a duplication of 1.4 Mb including PMP22 leads to the hereditary motor and sensory neuropathy type 1A and the reciprocal deletion to the hereditary neuropathy with liability to pressure palsies. However, also specific mutations in PMP22 itself can cause the identical syndromes [10]. Moreover, UBCA of several Mb in size have been reported, which surprisingly, do not have any clinical consequences [1,2]. At the same time, they are not pure copy number variants (CNV) such as those recently found for a cytogenetically visible amplified region in 8q21.2 [11]. In summary, there are genetically relevant regions which can be tolerated if ‘amplified’ as three or more copies; the reason for that is most likely that they do not comprise dosage sensitive genes. In summary, studying carriers of specific chromosomal imbalances can provide genotype- phenotype-correlations, and also give hints as to where copy-number-(in)sensitive genes are located in our genome. Where to Find Proximal Chromosome Imbalances in Humans. Centromere-near imbalances may principally appear as deletions or duplications. However, practically no reports of proximal deletions are available in the literature. The only exceptions are offspring of carriers with an sSMC formed by the Mc- Clintock mechanism [12], e.g., as reported for a child having the karyotype 47,XY,del(2) (p12p11.1) due to a maternal cytogenetic condition (47,XX,del(2) (p12p11.1),+r(2)(::p12→p11.1::) [13]. Only eight corresponding cases are available in the literature [6] and all these patients were severely affected. The best suited patients to study proximal duplications would be those with proximal intrachromosomal rearrangements, as direct or inverted duplications or unbalanced insertions, because these cases would be non mosaic [4]. However, such cases are scarce (summarized in Table 2). Most of these ~200 cases were only studied cytogenet-ically and no information on the molecular size of their duplicated region is available [6]. In contrast, the largest and best characterized group where to find proximal duplications are patients with sSMC [3-7,14-16]. Besides their cytogenetic characterization, more and more cases were characterized at the molecular level by array-comparative genomic hybridization (aCGH) studies [4,17,18]. However, when analyzing this group of patients one has to consider the following drawbacks: i) sSMC carriers may be mosaic with normal cell lines and/or may have different levels of mosaicism in different tissues; thus, harmful sSMC sizes may be rated as harmless [19], and ii) also harmless sSMC may be considered to be harmful if they appear together with a uniparental disomy (UPD) [20], or a mutation in a monogenic disorder gene [21]. Thus, results for regions including or excluding most likely dosage-sensitive genes, i.e., C-UBCA, have to be handled carefully. Nevertheless, sSMC carriers are much more frequent and better characterized on the molecular level than intrachromosomal duplications, and are thus used here as a model system for proximal duplications.

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