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No evidence of submicroscopic deletion or segmental uniparental disomy within the candidate regions 7p11.2‐p13 and 7q31‐qter in a series of non‐uniparental disomy Silver–Russell syndrome cases

To the Editor: Recently, different authors have demonstrated that 7–10% of patients with the phenotype of Silver–Russell syndrome (SRS) have maternal uniparental disomy for chromosome 7 (matUPD7), i.e. both homologues stem from the mother (1). Maternal isoor heterodisomy 7 causes intrauterine and post-natal growth retardation, together with typical phenotypic anomalies of SRS. Relative macrocephaly, a triangular face and a retarded bone age are clinical markers. In addition, less frequent findings in SRS are hemihypotrophy, areas of altered skin pigmentation or café-au-lait spots, short fifth fingers with clinodactyly, and developmental delay (2). Most cases of SRS occur sporadically, but autosomalrecessive, autosomal-dominant, and X-linked modes of inheritance have all been suggested from individual pedigrees (3–5). No single genetic cause for this syndrome has been found, but the evidence (in several individuals) of matUPD7 suggests that at least one imprinted gene on chromosome 7 is involved in the pathogenesis of SRS. Although the majority of SRS or SRS-like patients have a normal karyotype, a small number have been described with structural abnormalities of different chromosomes (7, 8, 15, 17, 18). However, to date, only chromosomes 7 and 17 have been repeatedly associated with patients with the SRS (6–13). Maternal UPD7 in SRS has involved the whole chromosome in the majority of subjects. However, the identification of SRS patients with anomalies of 7p11.2-p13 and 7q31-qter has suggested that these two intervals might be separate candidate regions for a gene or genes involved in SRS (13–17). In order to test the hypothesis that microdeletions, duplications or segmental matUPD within the 7p11.2-p13 or 7q31-qter regions are responsible for at least some cases of SRS, we investigated the transmission of selected microsatellite markers mapping to these two regions. The families had been referred to us from clinical geneticists all over Europe for investigation for complete matUPD7, and a normal biparental inheritance of chromosomes 7 was shown in all patients. We reinvestigated 107 patients and their parents using a set of 13 markers (see Table 1) from the 7p11.2-p13 and 7q31-qter regions. In all patients, the diagnosis was confirmed by a clinical geneticist, and all revealed (as minimal criteria) preand post-natal growth retardation, normal head circumference, a triangular face and clinodactyly. DNA was isolated from blood samples according to standard procedures. In eight families, the quality or amount of DNA was insufficient for investigation and it was not possible to obtain new samples for further analyses. In 95 out of 99 families, the markers tested did not show evidence for microdeletion, duplication or uniparental maternal disomy for the region 7p11.2-p13. In 83 of 99 families, these alterations were also excluded for the 7q31-qter region. In 16 families, the microsatellite markers were either not informative or it was not possible to exclude completely a uniparental disomy on the 7q31qter region. In four families the same was true for the 7p11.2-p13 region. Therefore, in these patients the markers tested could only exclude a microdeletion or duplication, but not a segmental matUPD7. Although the markers used were specific and the method sensitive, it should be considered that low-level mosaicism in UPD is often difficult to detect. The identification of genes associated with the SRS has been difficult, besides the clinical and Clin Genet 2003: 64: 252–254 Copyright # Blackwell Munksgaard 2003 Printed inDenmark. All rights reserved CLINICALGENETICS ISSN 0009-9163