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Constitutional de novo complex chromosomal rearrangements (CCRs) are a rare finding in patients with mild to severe mental retardation. CCRs pose a challenge to the clinical cytogeneticist: generally CCRs are assumed to be the cause of the observed phenotypic abnormalities, but the complex nature of these chromosomal changes often hamper the accurate delineation of the chromosomal breakpoints and the identification of possible imbalances. In a first step towards a more detailed molecular cytogenetic characterization of CCRs, we studied four de novo CCRs using multicolor fluorescent in situ hybridization (M-FISH), comparative genomic hybridization (CGH), and FISH with region specific probes. These methods allowed a more refined characterization of the breakpoints in three of the four CCRs. The occurrence of 7q breakpoints in three out of these four CCRs and in 30% of reported CCRs suggested preferential involvement of this chromosomal region in the formation of CCRs. Further analysis of these 7q breakpoints revealed a 2 Mb deletion at 7q21.11 in one patient and involvement of the same region in a cryptic insertion in a second patient. This particular region contains at least 5 candidate genes for mental retardation. The other patient had a breakpoint more proximal to this region. The present data together with these from the literature provide evidence that a region within 7q21.11 may be prone to breakage and formation of CCRs. © 2003 Wiley-Liss, Inc.

Merkel cell carcinoma (MCC) is a rare aggressive neuroendocrine tumor of the skin. Cytogenetic studies have indicated that deletions and unbalanced translocations involving chromosome 1 short arm material occur in 40% of the investigated cases. Recurrent chromosomal imbalances detected by comparative genomic hybridization (CGH) analysis were loss of 3p, 10q, 13q and 17p and gains of 1q, 3q, 5p and 8q. In order to study genomic aberrations occurring in MCC in further detail, we combined karyotyping, CGH and multiplex-fluorescence in situ hybridization (M-FISH), a strategy that proved to be successful in the analysis of other malignancies. Analysis of 6 MCC cell lines and 1 MCC tumor revealed mostly near-diploid karyotypes with an average of 5 chromosomal rearrangements. The observed karyotypic changes were heterogeneous, with 3–27 breakpoints per case, leading to imbalance of the involved chromosomal regions that was confirmed by CGH. Chromosomal rearrangements involving the short arm of chromosome 1, the long arm of chromosome 3 and gain of 5p material were the most frequently observed abnormalities in our study. In keeping with previous observations, this series of MCCs showed no evidence for high-level amplification. We provid a detailed description of chromosomal translocations occurring in MCC that could be useful to direct future intensive investigation of these chromosomal regions. © 2002 Wiley-Liss, Inc.

We describe the hitherto smallest interstitial 8p11.2 deletion in a patient with congenital spherocytosis, dysmorphic features, and growth delay in association with hypogonadotropic hypogonadism and anosmia. The latter features are characteristic for Kallmann syndrome. In contrast to the previously reported patients with 8p deletions, the present patient showed normal intelligence. Congenital spherocytosis is one of the most common hereditary hemolytic anemias. One of the three loci for congenital spherocytosis was assigned to chromosome 8p (located between 8p11.1 and 8p21) and mutations in or loss of the ankyrin-1 gene (ANK1) were identified. Molecular analysis confirmed the de novo loss of ANK1 in our patient. Kallmann syndrome, which is characterized by hypogonadotropic hypogonadism and anosmia, can be X-linked, autosomal dominant, or autosomal recessive. So far only the X-linked KAL1 gene has been identified. The present finding suggests an autosomal locus for Kallmann syndrome at 8p11.2. The simultaneous occurrence of congenital spherocytosis, Kallmann syndrome phenotype, dysmorphic features, and growth delay in this patient points to a new contiguous gene syndrome. © 2002 Wiley-Liss, Inc.

Merkel cell carcinoma (MCC) is a rare, highly metastatic skin tumor of neuroectodermal origin. The disease shares clinical and histopathological features with small cell lung carcinoma (SCLC). The genetic mechanisms underlying the development and tumor progression of MCC are poorly understood. We recently showed by comparative genomic hybridization (CGH) that the pattern of chromosomal abnormalities in MCC resembles that of SCLC. One of the most frequently observed losses involved the entire chromosome 10 or partial loss of the chromosome 10 long arm (33% of examined MCC cases). The PTEN tumor-suppressor gene has been mapped to 10q23.3 and was shown to be mutated in a variety of human cancers including SCLC. Germline PTEN mutations have been observed in familial predisposing cancer syndromes including Cowden disease. Interestingly, an association between Cowden syndrome and Merkel cell carcinoma has been reported. To study the possible role of PTEN in MCC oncogenesis, loss of heterozygosity (LOH) analysis for the 10q23 region was performed on 26 MCC tumor samples from 23 MCC patients. The PTEN locus was deleted in 9 of 21 (43%) informative MCC tumor samples [7 of 18 (39%) MCC patients]. Despite this high frequency of LOH at 10q23, mutation and homozygous deletion screening of the PTEN gene revealed only one tumor with a nonsense mutation and a second with a homozygous deletion of exon 9. These data suggest that either alternative mechanisms lead to inactivation of the PTEN gene or that other tumor-suppressor genes at chromosome 10 are implicated in the development of MCC. © 2001 Wiley-Liss, Inc.

We report on three brothers with mental retardation and a contracted CAG repeat in the androgen receptor (AR) gene. It is known that expansion of the CAG repeat in this gene leads to spinal and bulbar muscular atrophy (SBMA or Kennedy disease); however, contracted repeats have not yet been implicated in disease. As the range of the length of CAG repeats in the AR gene, like those of other genes associated with dynamic mutations, follows a normal distribution, the theoretical possibility of disease at both ends of the distribution should be considered. Am. J. Med. Genet. 85:209–213, 1999. © 1999 Wiley-Liss, Inc.

Purpose: To analyze the spectrum and frequency of NF1 mutations in exon 10bMethods: Mutation and sequence analysis was performed at the DNA and cDNA level.Results: We identified nine exon 10b mitations in 232 unrelated patients. Some mutations were recurrent (Y488C and L508P), other were unique (1465–1466insC and ivs10b + 2deITAAG). Surprisingly, at the RNA level, Y489c cause skipping of the last 62 nucleotides of exon 10b. another recurrent mutation, L508P, is undetectable by the Protein Truncation Test.Conclusion: As exon 10b show the highest mutation rate yet found in any of the 60 NF1 exon, it should be implemented with priorityin mutation analysis.

The clinical findings of eight families with Stickler syndrome were analyzed and compared with the results of linkage studies using a marker for the type II collagen gene (COL2A1). In six families, there was linkage of the phenotype to COL2A1. The manifestations of the affected individuals were similar to those of the original Stickler syndrome family [Stickler et al., Mayo. Clin. Proc. 40:433–455, 1965] and resembled the phenotype of the previously reported individuals or families with Stickler syndrome in which a dominant mutation in the COL2A1 gene has been identified. Linkage to COL2A1 was excluded in the two remaining families. The most striking difference between these two types of families was the absence of severe myopia and retinal detachment in the two unliked families. In the COL2A1 unlinked families, linkage of the phenotype to genes (COL11A1 and COL11A2) that encode proα chains of type XI collagen, a minor cartilage-specific collagen, was also excluded. Since Stickler syndrome can be produced by mutations in COL2A1, COL11A1, and COL11A2, our data suggest that there is at least a fourth locus for Stickler syndrome. Am. J. Med. Genet. 80:121–127, 1998. © 1998 Wiley-Liss, Inc.

We have characterised a point mutation causing the substitution of serine for glycine at position 661 of the 1(I) chain of type I collagen in a child with a severe form of osteogenesis imperfecta. An identical glycine substitution in the 2(I) chain was previously detected in a woman with post-menopausal osteoporosis. Two of her sons were heterozygous for the mutation and the third son was homozygous as a result of uniparental isodisomy. Biochemical profiles of the type I collagen heterotrimers were studied in each of the patients and compared with a control. Medium and cell-layer collagens were overmodified in all patients. Overmodification was obvious in the patient with the 1(I) mutation but mild in the patients with the 2(I) mutation, being slightly less evident in the heterozygote than in the homozygote. Investigation of the melting curves of the mutant collagen trimers in all three patients showed the same slight decrease in thermal stability and, hence, a lack of correlation with phenotypic severity. In contrast, the degree of overmodification of the collagen alpha chains was correlated with the phenotypic severity. The clinical observations in these patients illustrate the possibly predominant role of mutations in the collagen 1(I) chains over the same mutations in the 2(I) chains in determining the clinical outcome.

M-FISH analysis was performed on 18 neuroblastoma cell lines, which were previously studied with cytogenetic, standard FISH and CGH data. One of the most striking findings of this study was the detection of chromosome 2 short arm rearrangements in 61% of the investigated cell lines. These rearrangements resulted from translocations with various partner chromosomes. All translocations, except one were unbalanced, leading to the consistent gain of chromosome segment 2pter-p22. A cryptic balanced translocation t(2;4) was observed with a breakpoint located in the vicinity of MYCN in cell line NBL-S. Combination of M-FISH results together with cytogenetic, standard FISH and CGH data yielded the most comprehensive description of chromosome 2 short arm rearrangements, leading to a consistent gain of chromosome 2 short arm material. Med. Pediatr. Oncol. 35: 538–540, 2000. © 2000 Wiley-Liss, Inc.

Osteogenesis imperfecta (OI) type I is caused by a reduction of type I collagen resulting from the presence of a non-functional COL1A1 allele (null-allele). Owing to the lack of mutant mRNA, genomic screening of the COL1A1 and COL1A2 genes is required to identify a causal mutation, which is a costly and time consuming endeavour. We have developed an alternative approach for confirmation of a suspected diagnosis of OI type I based on the detection of a COL1A1 null-allele. Here we report the application of this COL1A1 null-allele detection test for prenatal diagnosis in a patient with OI type I in which it was shown that the fetus had inherited the normal COL1A1 allele from his affected mother and would not be affected with OI. Copyright © 1999 John Wiley & Sons, Ltd.

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