Abstract
Prader-Willi and Angelman syndromes are clinically distinct neurodevelopmental genetic disorders that map to 15q11.2-q13 locus. The common phenotypes are attributable to loss of expression of parentally specific imprinted genes inside this region, where the gene function is dependent on parental origin. Initial diagnosis was proved for the years by methylation pattern analyses of the SNRPN exon 1/promoter region within the PWS/AS critical domain. Apart from unifying methylation-specific PCR and allele specific real-time PCR with melt-curve analysis as the fundamental methods for suspected diagnosis confirmation, we combined several specifically methods used to clarify the molecular cause. In our study we had identified and genotyped 24 PWS and AS patients from 450 suspected. Applied cluster of methods-microsatellite analysis of SNPs within the chromosome 15, Methylation-specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) and UBE3A gene sequence analysis, enable us to determined atypical deletion that does not include common breakpoints, novel highly likely to be pathologic UBE3A mutation, uniparental heterodisomy together with partial isodisomy and epimutation without any deletions in the imprinting centre. We present genotype-phenotype correlation of all positive cases. In addition, we estimate the incidence for Slovakian population at 1 in 20,000 for PWS and 1 in 40,000 for AS.
Highlights
Syndromes (AS; OMIM: 105830) belong up to the bp sequence located 35 kb upstream to the SNRPN present to the best known imprinting disorders
Prader-Willi and Angelman syndromes are clinically distinct neurodevelopmental genetic disorders that map to 15q11.2-q13 locus
Microsatellite analysis was performed in all patients with confirmed PWS and AS diagnosis and with the parental blood samples available
Summary
Syndromes (AS; OMIM: 105830) belong up to the bp sequence located 35 kb upstream to the SNRPN present to the best known imprinting disorders. The common phenotypes of syndromes are attributed to loss of function of genes, which are under the control of a bipartite imprinting centre on chromosome 15 transcription start site (Buiting et al, 1999). Their function depends on parental establishment of the maternal epi-mark at the PWS-. Type I deletion is flanked by BP1-BP3 and encompasses genes from the NIPA family associated with deficits in adaptive behaviour (including mental-psychomotoric skills), autism spectrum, obsessive-compulsive behaviour and visual-motor integration. Patients with this type of deletion manifest more severe phenotype than patients with most common type II deletion (BP2-BP3) (Chai et al, 2003). Type III deletion (from BP1 to BP4) contributes only to 5% of all deletion cases and type IV deletion (from BP1 to BP5) has been reported only in inv dup (15) marker chromosomes or interstitial duplication and triplication cases (Roberts et al, 2003; Wandstrat et al, 1998)
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