Autism and duplication of 17q12q21.2 by array-CGH: a case report.

OBJECTIVE: Autism spectrum disorder (ASD) affects cognitive development and social interaction on different levels. Genetic and environmental factors are associated with secondary ASD. Genetic inheritance is mainly polygenic, and 10% are copy number variations (CNVs). Array comparative genomic hybridization (array-CGH) is used to identify CNVs. This report aimed to discuss autism spectrum disorder and its diagnosis by array comparative genomic hybridization, highlighting the association with the pathogenic duplication of 17q12q21.2. CASE DESCRIPTION: A male baby was born at 37 weeks' gestation by cesarean section. The child showed strabismus, cryptorchidism, hypertelorism, frontal bossing, and developmental delay, walking at 25 months and talking at 4 years. At the age of 2 years, array-CGH of peripheral blood revealed a 5.6-Mb 17q12q21.2 duplication or arr 17q12q21.2 (34,815,527-40,213.109)x3 encompassing 190 genes, including HNF-1B and LHX1. The child was clinically diagnosed with ASD. COMMENTS: Changes in the 17q12 segment, such as the duplication found, have been associated with the development of several problems in previous studies, mainly kidney diseases and behavioral disorders. Located at this chromosome region, HNF1's homeobox B codes a member of the superfamily containing homeodomain of transcription factors. Another gene associated with abnormalities in neurological development regarding 17q12 deletions is LHX1, as shown in this case study. LHX1 plays a role in the migration and differentiation of GABA neurons, modulating the survival of pre-optical interneurons, thus affecting cellular migration and distribution in the cortex. Changes in this control result in flaws in interneuron development, contributing to the pathophysiology of psychiatric diseases.

Autism and duplication of 17q12q21.2 by array-CGH: a case report / Autismo e duplicação da região 17q12q21.2 com array-CGH: um relato de caso

ABSTRACT Objective: Autism spectrum disorder (ASD) affects cognitive development and social interaction on different levels. Genetic and environmental factors are associated with secondary ASD. Genetic inheritance is mainly polygenic, and 10% are copy number variations (CNVs). Array comparative genomic hybridization (array-CGH) is used to identify CNVs. This report aimed to discuss autism spectrum disorder and its diagnosis by array comparative genomic hybridization, highlighting the association with the pathogenic duplication of 17q12q21.2. Case description: A male baby was born at 37 weeks' gestation by cesarean section. The child showed strabismus, cryptorchidism, hypertelorism, frontal bossing, and developmental delay, walking at 25 months and talking at 4 years. At the age of 2 years, array-CGH of peripheral blood revealed a 5.6-Mb 17q12q21.2 duplication or arr 17q12q21.2 (34,815,527-40,213.109)x3 encompassing 190 genes, including HNF-1B and LHX1. The child was clinically diagnosed with ASD. Comments: Changes in the 17q12 segment, such as the duplication found, have been associated with the development of several problems in previous studies, mainly kidney diseases and behavioral disorders. Located at this chromosome region, HNF1's homeobox B codes a member of the superfamily containing homeodomain of transcription factors. Another gene associated with abnormalities in neurological development regarding 17q12 deletions is LHX1, as shown in this case study. LHX1 plays a role in the migration and differentiation of GABA neurons, modulating the survival of pre-optical interneurons, thus affecting cellular migration and distribution in the cortex. Changes in this control result in flaws in interneuron development, contributing to the pathophysiology of psychiatric diseases.

RESUMO Objetivo: O transtorno do espectro autista (TEA) afeta o desenvolvimento cognitivo e a interação social em diferentes níveis. Fatores genéticos e ambientais estão associados a TEA secundário. A herança genética é principalmente poligênica e, em 10%, são variações do número de cópias (CNV). A hibridização genômica comparativa de array (array-CGH) é usada para identificar CNV. Este relato objetivou discutir o TEA e seu diagnóstico por array-CGH, destacando a associação com a duplicação patogênica do 17q12q21.2. Descrição do caso: Um bebê do sexo masculino nasceu com 37 semanas de gestação por cesariana. A criança apresentou atraso no desenvolvimento, andando aos dois anos e um mês e falando aos quatro, exibindo estrabismo, criptorquidia, hipertelorismo e saliência frontal. Aos dois anos, o array-CGH de sangue periférico revelou duplicação de 5,6 Mb 17q12q21.2 ou arr 17q12q21.2 (34.815.527-40.213.109) x3 abrangendo 190 genes, incluindo HNF1B e LHX1. A criança foi clinicamente diagnosticada com TEA. Comentários: Alterações no segmento 17q12, como a duplicação encontrada, têm sido associadas ao desenvolvimento de patologias renais e distúrbios comportamentais. Localizado nessa região cromossômica, o HNF1B codifica um membro da superfamília que contém o domínio dos fatores de transcrição. Outro gene foi associado a anormalidades neurológicas, em relação às deleções 17q12, o LHX1, como mostrado neste caso. O LHX1 desempenha um papel na migração e diferenciação dos neurônios GABA, modulando a sobrevivência dos interneurônios pré-ópticos e afetando, assim, a migração e distribuição celular no córtex. Mudanças nesse controle resultam em falhas no desenvolvimento dos interneurônios, contribuindo para a fisiopatologia das doenças psiquiátricas.

Short-term Prophylaxis for Delivery in Pregnant Women with Hereditary Angioedema with Normal C1-Inhibitor.

OBJECTIVE: To verify the efficacy of short-term prophylaxis for vaginal or cesarean section childbirth with plasma-derived C1-inhibitor concentrate in pregnant women. They should have hereditary angioedema (HAE) and normal plasma C1-inhibitor. METHODS: Case report of pregnant women diagnosed with HAE with normal C1-inhibitor who had been treated with intravenous C1-inhibitor concentrate for prophylaxis of angioedema attacks when hospitalized for delivery. The exon 9 of the Factor 12 (F12) genotyping gene was performed by automatic sequencing in all patients. RESULTS: Three cases of pregnant women with HAE with normal serum level of C1-inhibitor are reported. The genetic test detected the presence of a pathogenic mutation in the F12 gene. Deliveries occurred uneventfully and patients had no HAE symptoms in the following 72 hours. CONCLUSION: C1-inhibitor concentrate could be useful to prevent angioedema attacks during and after delivery.

OBJETIVO: Verificar a eficácia da profilaxia de curto prazo para o parto vaginal ou cesáreo com inibidor de C1 derivado de plasma concentrado em mulheres grávidas. Eles devem ter angioedema hereditário e inibidor normal de C1 no plasma. MéTODOS: Relato de caso de gestantes diagnosticadas com angioedema hereditário com inibidor de C1 normal que foram tratadas com inibidor intravenoso de concentrado de C1 para profilaxia de ataques de angioedema quando hospitalizadas para o parto. O exon 9 do gene de genotipagem do fator 12 (F12) foi realizado por sequenciamento automático em todos os pacientes. RESULTADOS: Três casos de gestantes com angioedema hereditário com nível sérico normal de inibidor de C1 são relatados. O teste genético detectou a presença de uma mutação patogênica no gene F12. Os partos ocorreram sem intercorrências e as pacientes não apresentaram sintomas hereditários de angioedema nas 72 horas seguintes. CONCLUSãO: O concentrado de inibidor de C1 pode ser útil para prevenir ataques de angioedema durante e após o parto.

Short-term prophylaxis for delivery in pregnant women with hereditary angioedema with normal C1-inhibitor / Profilaxia de curto prazo para o parto em grávidas com angioedema hereditário com inibidor de C1 normal

Abstract Objective To verify the efficacy of short-term prophylaxis for vaginal or cesarean section childbirth with plasma-derived C1-inhibitor concentrate in pregnant women. They should have hereditary angioedema (HAE) and normal plasma C1-inhibitor. Methods Case report of pregnant women diagnosed with HAE with normal C1- inhibitor who had been treated with intravenous C1-inhibitor concentrate for prophylaxis of angioedema attacks when hospitalized for delivery. The exon 9 of the Factor 12 (F12) genotyping gene was performed by automatic sequencing in all patients. Results Three cases of pregnant women with HAE with normal serum level of C1- inhibitor are reported. The genetic test detected the presence of a pathogenic mutation in the F12 gene. Deliveries occurred uneventfully and patients had no HAE symptoms in the following 72 hours. Conclusion C1-inhibitor concentrate could be useful to prevent angioedema attacks during and after delivery.

Resumo Objetivo Verificar a eficácia da profilaxia de curto prazo para o parto vaginal ou cesáreo com inibidor de C1 derivado de plasma concentrado em mulheres grávidas. Eles devem ter angioedema hereditário e inibidor normal de C1 no plasma. Métodos Relato de caso de gestantes diagnosticadas com angioedema hereditário com inibidor de C1 normal que foram tratadas com inibidor intravenoso de concentrado de C1 para profilaxia de ataques de angioedema quando hospitalizadas para o parto. O exon 9 do gene de genotipagem do fator 12 (F12) foi realizado por sequenciamento automático em todos os pacientes. Resultados Três casos de gestantes com angioedema hereditário com nível sérico normal de inibidor de C1 são relatados. O teste genético detectou a presença de uma mutação patogênica no gene F12. Os partos ocorreram sem intercorrências e as pacientes não apresentaram sintomas hereditários de angioedema nas 72 horas seguintes. Conclusão O concentrado de inibidor de C1 pode ser útil para prevenir ataques de angioedema durante e após o parto.

Study of angiopoietin and plasminogen genes in hereditary angioedema.

OBJECTIVE: To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS: Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS: DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION: Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

Study of angiopoietin and plasminogen genes in hereditary angioedema

SUMMARY OBJECTIVE To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. METHODS Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. RESULTS DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. CONCLUSION Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.

RESUMO OBJETIVO Investigar a presença das mutações no gene Angiopoietina (ANGPT1) e gene Plasminogênio (PLG) em pacientes com Angioedema Hereditário (AEH) com inibidor C1 esterase (C1-INH) normal e negativos para mutação do gene F12. MÉTODOS Foram avaliados pacientes com diagnóstico clínico de AEH sem deficiência ou disfunção de C1-INH e negativos para mutação do gene F12. Realizou-se extração, quantificação e diluição do DNA a uma concentração de 100 ng/uL, em seguida amplificação do DNA (PCR) para avaliação molecular do exon 2 do gene ANGPT1 e do exon 9 do gene PLG para identificação das mutações c.807G>T.p.A119S e c.988A>G p.K330E, respectivamente. O produto da PCR foi avaliado em eletroforese em gel de agarose 1%. Foi realizado o sequenciamento pelo método de Sanger. As análises dos eletroferogramas foram realizadas pelo programa FASTA®. RESULTADOS Foram sequenciadas amostras de 15 mulheres, idade entre 10 e 60 anos, com níveis séricos de inibidor de C1 esterase e C4 normais variando de 22 a 39mg/dL e 10 a 40mg/dL, respectivamente. Não foram identificadas mutações nos éxons analisados dos genes ANGPT1 e PLG. Entretanto no gene PLG foram encontrados polimorfismo de nucleotídeo único (SNP), em duas pacientes homozigotas e cinco heterozigotas. CONCLUSÃO Mais estudos sobre SNP são necessários para esclarecer estes achados pois eles podem ser utilizados como marcadores moleculares do AEH e alvo para novos tratamentos.

Diastrophic dysplasia: prenatal diagnosis and review of the literature.

CONTEXT: Diastrophic dysplasia is a type of osteochondrodysplasia caused by homozygous mutation in the gene DTDST (diastrophic dysplasia sulfate transporter gene). Abnormalities occurring particularly in the skeletal and cartilaginous system are typical of the disease, which has an incidence of 1 in 100,000 live births. CASE REPORT: The case of a pregnant woman, without any consanguineous relationship with her husband, whose fetus was diagnosed with skeletal dysplasia based on ultrasound findings and DNA tests, is described. An obstetric ultrasound scan produced in the 16th week of gestation revealed characteristics that guided the clinical diagnosis. Prominent among these characteristics were rhizomelia of the lower and upper limbs (shortening of the proximal portions) and mesomelia (shortening of the intermediate portions). Both upper limbs showed marked curvature, with the first finger of the upper limbs in abduction and clinodactyly of the fifth finger. Molecular analysis using the polymerase chain reaction (PCR) and gene sequencing detected mutations that had already been described in the literature for the gene DTDST, named c.862C > T and c.2147_2148insCT. Therefore, the fetus was a compound heterozygote, carrying two different mutations. CONCLUSIONS: Prenatal diagnosis of this condition allowed a more realistic interpretation of the prognosis, and of the couple's reproductive future. This case report shows the contribution of molecular genetics towards the prenatal diagnosis, for which there are few descriptions in the literature.