Diss. (sammanfattning) Uppsala : Uppsala universitet, 2005. / Härtill 6 uppsatser.

Foi realizado um estudo de prevalência em uma amostra de pacientes com neurofibromatose tipo 1, de um centro de referência do sul do Brasil localizado em um hospital público de atendimento terciário. O objetivo deste estudo foi criar um registro e caracterizar os pacientes clinicamente, determinando sua epidemiologia para servir de base para futuros estudos de correlação genótipo-fenótipo e protocolos clínicos. De acordo com os critérios de inclusão, os pacientes poderiam ter qualquer idade e ser de ambos os sexos, mas deveriam preencher critérios clínicos diagnósticos de NF1 de acordo com National Institutes of Health (NIH) Consensus Conference de 1988, estar clinicamente estáveis para participar do estudo e assinar termo de consentimento livre e esclarecido. Uma amostra consecutiva de pacientes com neurofibromatose tipo 1, atendidos entre janeiro de 2000 e maio de 2007 num hospital público terciário, foram avaliados. As avaliações incluíram: anamnese, heredograma, exame físico e colheita de dados do prontuário acerca dos exames rotineiramente realizados durante atendimento clínico (avaliação radiológica do crânio e esqueleto, tomografia computadorizada de crânio, ultra-sonografia de abdômen) e de dados históricos dos prontuários. De um total de 89 pacientes (provenientes de 62 famílias) incluídos no estudo, 37 (41,6%) eram do sexo masculino e 52 (58,4%) do sexo feminino. A idade média na avaliação foi 14,5 anos (DP 12,0; variação 0-47 anos), a idade média ao aparecimento do primeiro sintoma 2,9 anos (DP 5,1; variação 0-18 anos) e a idade média ao diagnóstico da doença foi 13,0 anos (DP 11,6; variação 0-47 anos). Dos 62 probandos, 44 (72,6%) tinham história familiar positiva para NF1. Avaliação psicométrica mostrou que dos 26 pacientes pediátricos submetidos a testes de QI 6 (23,1%) apresentavam algum déficit cognitivo e 11(43,3%), retardo mental. Em relação aos achados clássicos da síndrome observou-se que as freqüências de manchas café-com-leite, efélides, alterações esqueléticas, neurofibromas e nódulos de Lisch foram 98,9%, 79,8%, 10,1%, 51,7% e 34,1% respectivamente. Apesar de uma idade precoce ao reconhecimento do primeiro sintoma de NF1, o diagnóstico de indivíduos afetados na amostra, bem como a primeira avaliação em serviço de genética clínica, se deram muitos anos após. A literatura corrente registra diversos estudos nacionais e internacionais com diferentes metodologias e delineamentos relatando a freqüência de achados clínicos diagnósticos e complicações de NF1. Observa-se que a prevalência das manifestações da doença pode variar em diferentes populações e sua caracterização é importante para determinar as prioridades de avaliação em diferentes serviços de atendimento a estes pacientes. As diferenças encontradas neste estudo em relação à literatura poderão ser verificadas com maior precisão em estudos complementares com maior número de pacientes. A confirmação do fenótipo cognitivo da síndrome, através de teste psicométrico, sugere que todas as crianças afetadas pela doença sejam submetidas a este tipo de avaliação precocemente. Por fim, exames de imagem do tórax, crânio e abdômen para acompanhamento do surgimento de lesões em pacientes assintomáticos provavelmente não se justificam, devendo ser solicitados somente se houverem manifestações clínicas sugestivas de complicações específicas da NF1. / An prevalencia study from a reference center of Southern-Brazilian localized in a tertiary care public hospital, of the neurofibromatosis type 1 patients was carried out. The goal of this study was to create a registry, clinically characterize patients at determining their epidemiological so that it can serve as basis for future studies of the genotype-phenotype correlation and for protocols of future clinical studies. Each individual needed to meet the inclusion criteria: any age of years and any gender, to have a diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally (National Institutes of Health Consensus Conference de 1988) and the signing of an informed term consent. A consecutive sample of patients with the suspicion or diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally was invited for this study and evaluated after signature of informed consent. Patients had been seen in the outpatient clinic of the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre between January 2000 and May 2007. The assessment included: anamnesis, physical examination, family history, cranium and spine X-rays, brain CT scan, abdominal sonogram, IQ testing and in some cases retrospective review of information recorded in medical records. A total of 89 patients (from 62 families) were included in this study; 37 (41.6%) were male and 52 (58.4%) female. The mean age at evaluation was 14.5 years (SD 12.0: range 0-47 years), the mean age at the diagnosis of the first NF1 symptom was 2.9 years (SD 5.1; range 0-18 anos) and the mean age at NF1 diagnosis was 13.0 years (SD 11.6: range 0-47 anos). Of the 62 probands, 44(72.6%) had a positive family history of NF1. Cognitive evaluation of a subset of 26 pediatric patients showed that 6(23.1%) had a cognitive deficit and 11 (43.3%) were mentally retarded. Regarding classic NF1-related clinical findings, cafe-au-lait spots, freckling, skeletal dysplasia, neufibromas, Lisch nodules occurred in 98.9%, 79.8%, 10.1%, 51.7% and 34.1% of the patients, respectivelyds. Although the first sign of NF1 was recognized very early in life in most patients of this study, the diagnosis of the disease and first evaluation in a medical genetics service occurred many years after. Current literature cites several national and international studies reporting the frequency of clinical manifestations and complications of the disease that were conducted with distinct design and methodological strategies. The observed prevalence of disease manifestations is variable in these studies and its characterization is important to determine priorities in the routine clinical follow-up of such patients. Differences encountered in this study, in relation to the literature will have to be confirmed in a larger sample. The confirmation of the NF1 cognitive profile in a subset of pediatric patients suggests that all patients diagnosed with this condition should be evaluated early in their development. Finally, imaging studies of the chest, skull and abdomen for routine screening of disease complications in asymptomatic patients is probably not justified. Such evaluations should be reserved for patients manifesting symptoms associated to specific complications of NF1.

Foi realizado um estudo de prevalência em uma amostra de pacientes com neurofibromatose tipo 1, de um centro de referência do sul do Brasil localizado em um hospital público de atendimento terciário. O objetivo deste estudo foi criar um registro e caracterizar os pacientes clinicamente, determinando sua epidemiologia para servir de base para futuros estudos de correlação genótipo-fenótipo e protocolos clínicos. De acordo com os critérios de inclusão, os pacientes poderiam ter qualquer idade e ser de ambos os sexos, mas deveriam preencher critérios clínicos diagnósticos de NF1 de acordo com National Institutes of Health (NIH) Consensus Conference de 1988, estar clinicamente estáveis para participar do estudo e assinar termo de consentimento livre e esclarecido. Uma amostra consecutiva de pacientes com neurofibromatose tipo 1, atendidos entre janeiro de 2000 e maio de 2007 num hospital público terciário, foram avaliados. As avaliações incluíram: anamnese, heredograma, exame físico e colheita de dados do prontuário acerca dos exames rotineiramente realizados durante atendimento clínico (avaliação radiológica do crânio e esqueleto, tomografia computadorizada de crânio, ultra-sonografia de abdômen) e de dados históricos dos prontuários. De um total de 89 pacientes (provenientes de 62 famílias) incluídos no estudo, 37 (41,6%) eram do sexo masculino e 52 (58,4%) do sexo feminino. A idade média na avaliação foi 14,5 anos (DP 12,0; variação 0-47 anos), a idade média ao aparecimento do primeiro sintoma 2,9 anos (DP 5,1; variação 0-18 anos) e a idade média ao diagnóstico da doença foi 13,0 anos (DP 11,6; variação 0-47 anos). Dos 62 probandos, 44 (72,6%) tinham história familiar positiva para NF1. Avaliação psicométrica mostrou que dos 26 pacientes pediátricos submetidos a testes de QI 6 (23,1%) apresentavam algum déficit cognitivo e 11(43,3%), retardo mental. Em relação aos achados clássicos da síndrome observou-se que as freqüências de manchas café-com-leite, efélides, alterações esqueléticas, neurofibromas e nódulos de Lisch foram 98,9%, 79,8%, 10,1%, 51,7% e 34,1% respectivamente. Apesar de uma idade precoce ao reconhecimento do primeiro sintoma de NF1, o diagnóstico de indivíduos afetados na amostra, bem como a primeira avaliação em serviço de genética clínica, se deram muitos anos após. A literatura corrente registra diversos estudos nacionais e internacionais com diferentes metodologias e delineamentos relatando a freqüência de achados clínicos diagnósticos e complicações de NF1. Observa-se que a prevalência das manifestações da doença pode variar em diferentes populações e sua caracterização é importante para determinar as prioridades de avaliação em diferentes serviços de atendimento a estes pacientes. As diferenças encontradas neste estudo em relação à literatura poderão ser verificadas com maior precisão em estudos complementares com maior número de pacientes. A confirmação do fenótipo cognitivo da síndrome, através de teste psicométrico, sugere que todas as crianças afetadas pela doença sejam submetidas a este tipo de avaliação precocemente. Por fim, exames de imagem do tórax, crânio e abdômen para acompanhamento do surgimento de lesões em pacientes assintomáticos provavelmente não se justificam, devendo ser solicitados somente se houverem manifestações clínicas sugestivas de complicações específicas da NF1. / An prevalencia study from a reference center of Southern-Brazilian localized in a tertiary care public hospital, of the neurofibromatosis type 1 patients was carried out. The goal of this study was to create a registry, clinically characterize patients at determining their epidemiological so that it can serve as basis for future studies of the genotype-phenotype correlation and for protocols of future clinical studies. Each individual needed to meet the inclusion criteria: any age of years and any gender, to have a diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally (National Institutes of Health Consensus Conference de 1988) and the signing of an informed term consent. A consecutive sample of patients with the suspicion or diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally was invited for this study and evaluated after signature of informed consent. Patients had been seen in the outpatient clinic of the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre between January 2000 and May 2007. The assessment included: anamnesis, physical examination, family history, cranium and spine X-rays, brain CT scan, abdominal sonogram, IQ testing and in some cases retrospective review of information recorded in medical records. A total of 89 patients (from 62 families) were included in this study; 37 (41.6%) were male and 52 (58.4%) female. The mean age at evaluation was 14.5 years (SD 12.0: range 0-47 years), the mean age at the diagnosis of the first NF1 symptom was 2.9 years (SD 5.1; range 0-18 anos) and the mean age at NF1 diagnosis was 13.0 years (SD 11.6: range 0-47 anos). Of the 62 probands, 44(72.6%) had a positive family history of NF1. Cognitive evaluation of a subset of 26 pediatric patients showed that 6(23.1%) had a cognitive deficit and 11 (43.3%) were mentally retarded. Regarding classic NF1-related clinical findings, cafe-au-lait spots, freckling, skeletal dysplasia, neufibromas, Lisch nodules occurred in 98.9%, 79.8%, 10.1%, 51.7% and 34.1% of the patients, respectivelyds. Although the first sign of NF1 was recognized very early in life in most patients of this study, the diagnosis of the disease and first evaluation in a medical genetics service occurred many years after. Current literature cites several national and international studies reporting the frequency of clinical manifestations and complications of the disease that were conducted with distinct design and methodological strategies. The observed prevalence of disease manifestations is variable in these studies and its characterization is important to determine priorities in the routine clinical follow-up of such patients. Differences encountered in this study, in relation to the literature will have to be confirmed in a larger sample. The confirmation of the NF1 cognitive profile in a subset of pediatric patients suggests that all patients diagnosed with this condition should be evaluated early in their development. Finally, imaging studies of the chest, skull and abdomen for routine screening of disease complications in asymptomatic patients is probably not justified. Such evaluations should be reserved for patients manifesting symptoms associated to specific complications of NF1.

Foi realizado um estudo de prevalência em uma amostra de pacientes com neurofibromatose tipo 1, de um centro de referência do sul do Brasil localizado em um hospital público de atendimento terciário. O objetivo deste estudo foi criar um registro e caracterizar os pacientes clinicamente, determinando sua epidemiologia para servir de base para futuros estudos de correlação genótipo-fenótipo e protocolos clínicos. De acordo com os critérios de inclusão, os pacientes poderiam ter qualquer idade e ser de ambos os sexos, mas deveriam preencher critérios clínicos diagnósticos de NF1 de acordo com National Institutes of Health (NIH) Consensus Conference de 1988, estar clinicamente estáveis para participar do estudo e assinar termo de consentimento livre e esclarecido. Uma amostra consecutiva de pacientes com neurofibromatose tipo 1, atendidos entre janeiro de 2000 e maio de 2007 num hospital público terciário, foram avaliados. As avaliações incluíram: anamnese, heredograma, exame físico e colheita de dados do prontuário acerca dos exames rotineiramente realizados durante atendimento clínico (avaliação radiológica do crânio e esqueleto, tomografia computadorizada de crânio, ultra-sonografia de abdômen) e de dados históricos dos prontuários. De um total de 89 pacientes (provenientes de 62 famílias) incluídos no estudo, 37 (41,6%) eram do sexo masculino e 52 (58,4%) do sexo feminino. A idade média na avaliação foi 14,5 anos (DP 12,0; variação 0-47 anos), a idade média ao aparecimento do primeiro sintoma 2,9 anos (DP 5,1; variação 0-18 anos) e a idade média ao diagnóstico da doença foi 13,0 anos (DP 11,6; variação 0-47 anos). Dos 62 probandos, 44 (72,6%) tinham história familiar positiva para NF1. Avaliação psicométrica mostrou que dos 26 pacientes pediátricos submetidos a testes de QI 6 (23,1%) apresentavam algum déficit cognitivo e 11(43,3%), retardo mental. Em relação aos achados clássicos da síndrome observou-se que as freqüências de manchas café-com-leite, efélides, alterações esqueléticas, neurofibromas e nódulos de Lisch foram 98,9%, 79,8%, 10,1%, 51,7% e 34,1% respectivamente. Apesar de uma idade precoce ao reconhecimento do primeiro sintoma de NF1, o diagnóstico de indivíduos afetados na amostra, bem como a primeira avaliação em serviço de genética clínica, se deram muitos anos após. A literatura corrente registra diversos estudos nacionais e internacionais com diferentes metodologias e delineamentos relatando a freqüência de achados clínicos diagnósticos e complicações de NF1. Observa-se que a prevalência das manifestações da doença pode variar em diferentes populações e sua caracterização é importante para determinar as prioridades de avaliação em diferentes serviços de atendimento a estes pacientes. As diferenças encontradas neste estudo em relação à literatura poderão ser verificadas com maior precisão em estudos complementares com maior número de pacientes. A confirmação do fenótipo cognitivo da síndrome, através de teste psicométrico, sugere que todas as crianças afetadas pela doença sejam submetidas a este tipo de avaliação precocemente. Por fim, exames de imagem do tórax, crânio e abdômen para acompanhamento do surgimento de lesões em pacientes assintomáticos provavelmente não se justificam, devendo ser solicitados somente se houverem manifestações clínicas sugestivas de complicações específicas da NF1. / An prevalencia study from a reference center of Southern-Brazilian localized in a tertiary care public hospital, of the neurofibromatosis type 1 patients was carried out. The goal of this study was to create a registry, clinically characterize patients at determining their epidemiological so that it can serve as basis for future studies of the genotype-phenotype correlation and for protocols of future clinical studies. Each individual needed to meet the inclusion criteria: any age of years and any gender, to have a diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally (National Institutes of Health Consensus Conference de 1988) and the signing of an informed term consent. A consecutive sample of patients with the suspicion or diagnosis of neurofibromatosis type 1, defined by standard clinical criteria defined internationally was invited for this study and evaluated after signature of informed consent. Patients had been seen in the outpatient clinic of the Medical Genetics Service of the Hospital de Clínicas de Porto Alegre between January 2000 and May 2007. The assessment included: anamnesis, physical examination, family history, cranium and spine X-rays, brain CT scan, abdominal sonogram, IQ testing and in some cases retrospective review of information recorded in medical records. A total of 89 patients (from 62 families) were included in this study; 37 (41.6%) were male and 52 (58.4%) female. The mean age at evaluation was 14.5 years (SD 12.0: range 0-47 years), the mean age at the diagnosis of the first NF1 symptom was 2.9 years (SD 5.1; range 0-18 anos) and the mean age at NF1 diagnosis was 13.0 years (SD 11.6: range 0-47 anos). Of the 62 probands, 44(72.6%) had a positive family history of NF1. Cognitive evaluation of a subset of 26 pediatric patients showed that 6(23.1%) had a cognitive deficit and 11 (43.3%) were mentally retarded. Regarding classic NF1-related clinical findings, cafe-au-lait spots, freckling, skeletal dysplasia, neufibromas, Lisch nodules occurred in 98.9%, 79.8%, 10.1%, 51.7% and 34.1% of the patients, respectivelyds. Although the first sign of NF1 was recognized very early in life in most patients of this study, the diagnosis of the disease and first evaluation in a medical genetics service occurred many years after. Current literature cites several national and international studies reporting the frequency of clinical manifestations and complications of the disease that were conducted with distinct design and methodological strategies. The observed prevalence of disease manifestations is variable in these studies and its characterization is important to determine priorities in the routine clinical follow-up of such patients. Differences encountered in this study, in relation to the literature will have to be confirmed in a larger sample. The confirmation of the NF1 cognitive profile in a subset of pediatric patients suggests that all patients diagnosed with this condition should be evaluated early in their development. Finally, imaging studies of the chest, skull and abdomen for routine screening of disease complications in asymptomatic patients is probably not justified. Such evaluations should be reserved for patients manifesting symptoms associated to specific complications of NF1.

Made available in DSpace on 2016-01-26T12:51:17Z (GMT). No. of bitstreams: 1 joaorobertoantonio_tese.pdf: 4793958 bytes, checksum: 56e42b3687617eb1ad6580c037e8fee1 (MD5) Previous issue date: 2001-08-30 / Neurofibromatosis (NF) is a neuroectodermal abnormality composed of a set of conditions having clinical manifestations which mainly affect the skin, eyes, bones, nervous system and eventually have repercussions on other internal organs. Its inheritance pattern is normally autosomally dominant and it has been considered one of the most frequent genetic diseases in the human race with a high penetration and variable expressiveness. This work studies the genetical-clinical aspects, makes a quantitative evaluation of the mastocytes and the extracellular matrix in neurofibromas in a group of thirty patients diagnosed with NF-1 and makes a comparison with a control group of ten normal individuals. The genetical-clinical evaluation confirmed the diagnosis of type 1 NF (NF-1) in all the patients. The main characteristics were neurofibromas, caféau-lait spots (CLS), Lisch nodules and axial or inguinal freckles. The multiple neurofibromas and Lisch nodules were considered to be exclusive to NF-1. Macrocephaly, in isolation, was not sufficient for the diagnosis of NF-1 and the other characteristics observed were considered complications. With the tissue from biopsies of both normal skin and neurofibromas of these patients, ten histologic sections were obtained. These were stained using hematoxylin-eosine, Gömöri trichrome, pricrosirius-hematoxylin, silver and iron-hematoxylin impregnation to evaluate the components of the extracellular matrix and staining using Toluidine blue to count the mastocytes. There was a significant increase in the number of mastocytes and the extracellular matrix was altered compared to the normal skin. This alteration was seen by the high cellularity associated with an increased density of fibrous components, specifically collagen type III, the scarcity or almost nonexistence of amorphous fundamental substance and the lack of elastic tissue. These findings seem to have an important role in the formation of neurofibromas and can help in the treatment of NF. / A Neurofibromatose (NF), é uma anormalidade neuroectodérmica constituída por um conjunto de condições com manifestações clínicas que comprometem principalmente a pele, olhos, ossos, sistema nervoso e, eventualmente, com repercussões aos outros órgãos internos. Seu padrão de herança é autossômica dominante e tem sido considerada uma das mais freqüente na espécie humana com penetrância elevada e expressividade variável. No presente trabalho, estudou-se os aspectos genético-clínicos, realizou-se a avaliação quantitativa dos mastócitos e da matriz extracelular em neurofibromas de um grupo de 30 pacientes diagnosticados como NF-1 e comparou-se com o grupo controle constituído de 10 indivíduos normais. A avaliação genético-clínica confirmou o diagnóstico de NF-1 em todos os pacientes. As características principais ou major foram os neurofibromas, MCCL, nódulo de Lisch e sardas axilares ou inguinais. Os neurofibromas múltiplos e os nódulos de Lisch foram considerados exclusivos de NF-1. A macrocefalia, quando isoladamente, não demonstrou ser suficiente para o diagnóstico de NF1 e as outras características foram consideradas como complicações. Em material obtido de biópsias de pele normal e de neurofibromas desses pacientes, realizou-se 10 cortes histológicos os quais foram submetidos às técnicas de coloração pela hematoxilina-eosina, tricrômio de gomori, tricrômio do pricrosirius-hematoxilina, impregnação pela prata e hematoxilinaférrica para a avaliação dos componentes da matriz extracelular e pela coloração com o azul de toluidina para a contagem de mastócitos. Houve diferença significativa no número dos mastócitos que encontraram-se aumentados e, quanto a matriz extracelular, apresentou-se alterada em comparação com a pele normal pela alta celularidade associada à elevada densidade dos componentes fibrosos, particularmente do colágeno tipo III, com escassez ou quase ausência de substância fundamental amorfa e ausência de material elástico. Tais achados parecem ter um papel significativo na formação dos neurofibromas e podem colaborar na terapêutica da NF.

<p>Microarray-based comparative genomic hybridization (array-CGH) has emerged as a versatile platform with a wide range of applications in molecular genetics. This thesis focuses on the development of array-CGH with a specific aim to approach disease-related questions through improved strategies in array construction and enhanced resolution of analysis. In <b>paper I</b>, we applied an array covering 11 Mb of 22q, encompassing the <i>NF2</i> locus, for deletion detection in sporadic schwannoma. Hemizygous deletions and tumor heterogeneity were identified. Array-CGH was established as a reliable platform for detection of DNA dosage alterations. <b>Paper II</b> described the construction of the<i> NF2</i> gene-specific microarray for high-resolution scanning of deletions in the <i>NF2</i> locus. We report a novel PCR-based non-redundant strategy for microarray fabrication, which considerably improved the sensitivity and reliability of deletion detection. <b>Paper III</b> reported the first tiling-path array comprehensively covering a human chromosome. The usefulness of the 22q-array was demonstrated by applying it to detect DNA dosage-alterations in 22q-associated disorders. In <b>paper IV</b>, we optimized array-CGH protocols for deletion detection in 22q11 deletion-syndrome. We showed that genomic and cDNA clones are not optimal for analysis of 22q11 locus and that PCR-based non-redundant strategy is reliable for deletion detection in such regions. In <b>paper V</b>, we utilized the 22q-array for understanding the genetic basis of schwannomatosis. Two commonly deleted regions were identified within the <i>IGL</i> and the <i>GSTT1/CABIN1</i> loci. Further investigations using high-resolution arrays, bioinformatic analysis and mutational screening were performed. Missense mutations, specific to the schwannomatosis- and NF2 samples, were identified in the <i>CABIN1 </i>gene. <b>Paper VI</b> described the first array-CGH study for comprehensive and high-resolution profiling of deletions spanning the 17q11 locus. Both typical and atypical deletions were identified in NF1 samples. Bioinformatic analysis revealed novel segmental duplications, which can potentially mediate 17q11 deletions.</p>

Microarray-based comparative genomic hybridization (array-CGH) has emerged as a versatile platform with a wide range of applications in molecular genetics. This thesis focuses on the development of array-CGH with a specific aim to approach disease-related questions through improved strategies in array construction and enhanced resolution of analysis. In <b>paper I</b>, we applied an array covering 11 Mb of 22q, encompassing the NF2 locus, for deletion detection in sporadic schwannoma. Hemizygous deletions and tumor heterogeneity were identified. Array-CGH was established as a reliable platform for detection of DNA dosage alterations. <b>Paper II</b> described the construction of the NF2 gene-specific microarray for high-resolution scanning of deletions in the NF2 locus. We report a novel PCR-based non-redundant strategy for microarray fabrication, which considerably improved the sensitivity and reliability of deletion detection. <b>Paper III</b> reported the first tiling-path array comprehensively covering a human chromosome. The usefulness of the 22q-array was demonstrated by applying it to detect DNA dosage-alterations in 22q-associated disorders. In <b>paper IV</b>, we optimized array-CGH protocols for deletion detection in 22q11 deletion-syndrome. We showed that genomic and cDNA clones are not optimal for analysis of 22q11 locus and that PCR-based non-redundant strategy is reliable for deletion detection in such regions. In <b>paper V</b>, we utilized the 22q-array for understanding the genetic basis of schwannomatosis. Two commonly deleted regions were identified within the IGL and the GSTT1/CABIN1 loci. Further investigations using high-resolution arrays, bioinformatic analysis and mutational screening were performed. Missense mutations, specific to the schwannomatosis- and NF2 samples, were identified in the CABIN1 gene. <b>Paper VI</b> described the first array-CGH study for comprehensive and high-resolution profiling of deletions spanning the 17q11 locus. Both typical and atypical deletions were identified in NF1 samples. Bioinformatic analysis revealed novel segmental duplications, which can potentially mediate 17q11 deletions.