Cryptic chromosome abnormalities in idiopathic mental retardation

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Molecular Medicine

Sammanfattning: Mental retardation is a common disorder, affecting 1-3% of the population. In spite of improved diagnostic tools, the etiology can still not be established in half of the cases. Several lines of evidence indicate a genetic origin in a significant number of individuals with idiopathic mental retardation. The subtelomeric regions are gene rich, difficult to analyze with conventional cytogenetic methods and are often involved in rearrangements. Recent investigations have demonstrated subtelomeric abnormalities in a significant proportion of cases with idiopathic MR. We analyzed 111 individuals with idiopathic MR using subtelomeric FISH probes. Ten cryptic subtelomeric rearrangements were found (9%) - five de novo deletions, one unbalanced de novo translocation, three unbalanced inherited translocations and one unbalanced inherited recombinant chromosome. Dysmorphic features were present in all patients with detected subtelomeric rearrangements. In addition, fifty of the patients were screened for interstitial rearrangements with spectral karyotyping, but no aberrations could be found. However, spectral karyotyping could detect the subtelomeric rearrangement in three of the four unbalanced translocations. Two cases with detected cryptic subtelomeric deletions were further analyzed with FISH to determine the size of the deletions and to identify the genes involved. The deletion of terminal 6p was 1.8 Mb, and encompassed five characterized genes. Two of the deleted genes were forkhead transcription factors, members of a gene family involved in embryonic development of different tissues, body axis and midline structures. The size of the terminal 22q deletion was estimated to 100 kb, and three genes were affected by the deletion. ProSAP2, expressed in brain and involved in the cytoskeleton at excitatory synapses, was disrupted in the patient and constitute a strong candidate gene for the 22q13 deletion phenotype. Two isochromosomes, i(9p) and i(9q) were detected in a healthy woman with repeated miscarriages. Analysis with polymorphic DNA markers of the woman and her parents demonstrated maternal unipatental disomy 9. Since the woman was healthy, despite the fact that she lacks paternal genes from chromosome 9, this case supports the theory of absence of maternally imprinted genes on chromosome 9. Twelve patients with supernumerary ring chromosomes were analyzed with micro-FISH, and the exact origin was established. In addition, in eight of the families, microsatellite analysis was performed, and in one patient maternal uniparental disomy 9 was detected. In this case, the symptoms probably are correlated to the presence of the supernumerary ring chromosome, since there seems to be no maternally imprinted genes on chromosome 9. One case of uniparental disomy found in eight analyzed families also supports the theory of marker chromosomes affecting meiotic segregation. The result of this study supports the clinical use of subtelomeric FISH screening in individuals with idiopathic MR. The detection of an inherited rearrangement gives the extended family . the option of carrier detection and prenatal diagnosis. Detailed characterization of chromosome aberrations makes gene identification and genotypelphenotype correlation on gene level possible.

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