RESUMO
Lissencephaly comprises a spectrum of brain malformations due to impaired neuronal migration in the developing cerebral cortex. Classical lissencephaly is characterized by smooth cerebral surface and cortical thickening that result in seizures, severe neurological impairment and developmental delay. Mutations in the X-chromosomal gene DCX, encoding doublecortin, is the main cause of classical lissencephaly. Much of our knowledge about DCX-associated lissencephaly comes from post-mortem analyses of patient's brains, mainly since animal models with DCX mutations do not mimic the disease. In the absence of relevant animal models and patient brain specimens, we took advantage of induced pluripotent stem cell (iPSC) technology to model the disease. We established human iPSCs from two males with mutated DCX and classical lissencephaly including smooth brain and abnormal cortical morphology. The disease was recapitulated by differentiation of iPSC into neural cells followed by expression profiling and dissection of DCX-associated functions. Here we show that neural stem cells, with absent or reduced DCX protein expression, exhibit impaired migration, delayed differentiation and deficient neurite formation. Hence, the patient-derived iPSCs and neural stem cells provide a system to further unravel the functions of DCX in normal development and disease.
Assuntos
Lisencefalia/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/fisiologia , Neuropeptídeos/genética , Neuropeptídeos/fisiologia , Encéfalo/metabolismo , Diferenciação Celular/genética , Movimento Celular/genética , Células Cultivadas , Córtex Cerebral/metabolismo , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Fibroblastos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Lactente , Recém-Nascido , Lisencefalia/metabolismo , Masculino , Células-Tronco Neurais/metabolismo , Neuritos/fisiologia , Neurogênese/genética , Neurônios/metabolismo , Neuropeptídeos/metabolismoRESUMO
The environmental contributions to autism spectrum disorder (ASD) and their informative content for diagnosing the condition are still largely unknown. The objective of this study was to investigate associations between early medical events and ASD, as well as autistic traits, in twins, to test the hypothesis of a cumulative environmental effect on ASD risk. A total of 80 monozygotic (MZ) twin pairs (including a rare sample of 13 twin pairs discordant for clinical ASD) and 46 dizygotic (DZ) twin pairs with varying autistic traits, were examined for intra-pair differences in early medical events (for example, obstetric and neonatal factors, first year infections). First, differences in early medical events were investigated using multisource medical records in pairs qualitatively discordant for ASD. The significant intra-pair differences identified were then tested in relation to autistic traits in the remaining sample of 100 pairs, applying generalized estimating equations analyses. Significant association of the intra-pair differences in the MZ pairs were found for the cumulative load of early medical events and clinical ASD (Z=-2.85, P=0.004) and autistic traits (ß=78.18, P=0.002), as well as infant dysregulation (feeding, sleeping abnormalities, excessive crying and worriedness), when controlling for intelligence quotient and attention deficit hyperactivity disorder comorbidity. The cumulative load of early medical events in general, and infant dysregulation in particular, may index children at risk of ASD owing to non-shared environmental contributions. In clinical practice, these findings may facilitate screening and early detection of ASD.
Assuntos
Transtorno Autístico/psicologia , Meio Ambiente , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adolescente , Adulto , Índice de Apgar , Asma/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/psicologia , Transtorno Autístico/epidemiologia , Peso ao Nascer , Apresentação Pélvica/epidemiologia , Hemorragia Cerebral/epidemiologia , Criança , Eczema/epidemiologia , Epilepsia/epidemiologia , Transtornos de Alimentação na Infância/epidemiologia , Feminino , Sofrimento Fetal/epidemiologia , Gastroenterite/epidemiologia , Cardiopatias Congênitas/epidemiologia , Humanos , Hidrocefalia/epidemiologia , Hiperbilirrubinemia Neonatal/epidemiologia , Hipersensibilidade/epidemiologia , Hipoglicemia/epidemiologia , Masculino , Microcefalia/epidemiologia , Otite Média/epidemiologia , Oxigenoterapia , Gravidez , Pielonefrite/epidemiologia , Sepse/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Suécia/epidemiologia , Trombocitopenia/epidemiologia , Transtornos da Visão/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: To analyze whether the frequency of autism spectrum disorder (ASD) in a cohort of Swedish children differs between those exposed to ultrasound in the 12(th) week and those exposed to ultrasound in the 18(th) week of gestation. METHODS: The study cohort consisted of approximately 30 000 children born between 1999 and 2003 to mothers who had been randomized to a prenatal ultrasound examination at either 12 or 18 weeks' gestation as part of the framework for a study on nuchal translucency screening. The outcome measure in the present study was the rate of ASD diagnoses among the children. Information on ASD diagnoses was based on data from the Swedish social insurance agency concerning childcare allowance granted for ASD. RESULTS: Between 1999 and 2003, a total of 14 726 children were born to women who underwent a 12-week ultrasound examination and 14 596 to women who underwent an 18-week ultrasound examination. Of these, 181 (1.2%) and 176 (1.2%) children, respectively, had been diagnosed with ASD. There was no difference in ASD frequency between the early and late ultrasound groups. CONCLUSIONS: Women subjected to at least one prenatal ultrasound examination at either 12 or 18 weeks' gestation had children with similar rates of ASD. However, this result reflects routine care 10-15 years ago in Sweden. Today, higher intensity ultrasound scans are performed more frequently, at earlier stages during pregnancy and for non-medical purposes, implying longer exposure time for the fetus. This change in the use of ultrasound necessitates further follow-up study of the possible effects that high exposure to ultrasound during the gestational period has on the developing brain. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.
Assuntos
Transtorno do Espectro Autista/epidemiologia , Primeiro Trimestre da Gravidez , Segundo Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Ultrassonografia Pré-Natal , Adulto , Transtorno do Espectro Autista/etiologia , Criança , Feminino , Seguimentos , Idade Gestacional , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores de Risco , Suécia/epidemiologia , Ultrassonografia Pré-Natal/efeitos adversosRESUMO
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
Assuntos
Hidranencefalia/diagnóstico , Hidranencefalia/genética , Hidrocefalia/diagnóstico , Hidrocefalia/genética , Proteínas de Membrana Transportadoras/genética , Mutação , Receptores Virais/genética , Doenças Vasculares/diagnóstico , Doenças Vasculares/genética , Alelos , Encéfalo , Pré-Escolar , Análise Mutacional de DNA , Éxons , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Linhagem , Fenótipo , Irmãos , SíndromeRESUMO
Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Proteínas de Ligação a DNA/genética , Face/anormalidades , Estudos de Associação Genética , Doenças Hematológicas/diagnóstico , Doenças Hematológicas/genética , Mutação , Proteínas de Neoplasias/genética , Doenças Vestibulares/diagnóstico , Doenças Vestibulares/genética , Fácies , Feminino , Humanos , Masculino , Fenótipo , Análise de Sequência de DNARESUMO
Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
Assuntos
Anormalidades Múltiplas/genética , Agenesia do Corpo Caloso/genética , Transtorno Autístico/genética , Proteínas de Ligação a DNA/genética , Deficiência Intelectual/genética , Distúrbios da Fala/genética , Fatores de Transcrição/genética , Adulto , Pré-Escolar , Haploinsuficiência , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Microarray-based comparative genomic hybridization (array-CGH) enables genomewide investigation of copy-number changes at high resolution and has recently been implemented as a clinical diagnostic tool. In this study we evaluate the usefulness of high-resolution arrays as a diagnostic tool in our laboratory and investigate the diagnostic yield in the first 160 patients who were clinically referred for investigation of developmental delay (DD)/multiple congenital anomalies (MCA). During this period both 38K BAC-arrays and 244K oligonucleotide-arrays were used. Copy-number variations (CNVs) not previously reported as normal variants were detected in 22.5% of cases. In 13.1% the aberrations were considered causal to the phenotype and in 9.4% the clinical significance was uncertain. There was no difference in diagnostic yield between patients with mild, moderate or severe DD. Although the effective resolution of the 244K oligonucleotide-arrays was higher than the 38K BAC-array, the diagnostic yield of both platforms was approximately equal and no causal aberrations <300 kb were detected in this patient cohort. We experienced that increasing the resolution of a whole genome screen in the diagnostic setting has its drawback of detecting an increased number of CNVs with uncertain contribution to a phenotype. Based on our experiences, array-CGH is recommended as the first-step analysis in the genetic evaluation of patients with DD and/or MCA.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Testes Genéticos/métodos , Cariotipagem , Técnicas de Diagnóstico Molecular , Anormalidades Múltiplas/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Deficiências do Desenvolvimento/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Cariotipagem/métodos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Índice de Gravidade de Doença , Adulto JovemRESUMO
The chromosome region 22q11.2 has long been recognized to be susceptible to genomic rearrangement. More recently, this genomic instability has been shown to extend distally (involving LCR22E-H) to the commonly deleted/duplicated region. To date, 21 index cases with 'distal' 22q11.2 duplications have been reported. We report on the clinical and molecular characterization of 16 individuals with distal 22q11.2 duplications identified by DNA microarray analysis. Two of the individuals have been partly described previously. The clinical phenotype varied among the patients in this study, although the majority displayed various degrees of developmental delay and speech disturbances. Other clinical features included behavioral problems, hypotonia, and dysmorphic facial features. Notably, none of the patients was diagnosed with a congenital heart defect. We found a high degree of inherited duplications. Additional copy number changes of unclear clinical significance were identified in 5 of our patients, and it is possible that these may contribute to the phenotypic expression in these patients as has been suggested recently in a 2-hit 'digenic' model for 16p12.1 deletions. The varied phenotypic expression and incomplete penetrance observed for distal 22q11.2 duplications makes it exceedingly difficult to ascribe pathogenicity for these duplications. Given the observed enrichment of the duplication in patient samples versus healthy controls, it is likely that distal 22q11.2 duplications represent a susceptibility/risk locus for speech and mild developmental delay.
RESUMO
We have investigated three patients with 21q deletions, two with developmental delay, dysmorphic features and internal organ malformations, and one with cognitive function within the normal range but with some deficits in gross and fine motor development. All aberrations were characterized by array-comparative genomic hybridization (array-CGH). In addition, extensive fluorescence in situ hybridization (FISH) mapping on metaphase chromosomes and mechanically stretched chromosomes was performed on patient 1 who had an extremely complex intrachromosomal rearrangement with 16 breakpoints, four deletions and four duplications. Patients 2 and 3 had interstitial deletions comprising 21q21.1-21q22.11 and 21q11.2-21q21.3, respectively. Partial deletions of 21q are rare and these patients display a highly variable phenotype depending on the size and position of the deletion. A review of the literature identified 38 cases with pure 21q deletions. Twenty-three of these had reliable mapping data. The combined information of present and previous cases suggests that the ITSN1 gene is involved in severe mental retardation in patients with 21q deletion. In addition, a critical region of 0.56 Mb containing four genes, KCNE1, DSCR1, CLIC6 and RUNX1, is associated with severe congenital heart defects, and deletions of the most proximal 15-17 Mb of 21q is associated with mild or no cognitive impairment, but may lead to problems with balance and motor function.
Assuntos
Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 21 , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/patologia , Hibridização Genômica Comparativa , Feminino , Humanos , MasculinoRESUMO
Array CGH (comparative genomic hybridization) screening of large patient cohorts with mental retardation and/or multiple congenital anomalies (MR/MCA) has led to the identification of a number of new microdeletion and microduplication syndromes. Recently, a recurrent copy number variant (CNV) at chromosome 16p11.2 was reported to occur in up to 1% of autistic patients in three large autism studies. In the screening of 4284 patients with MR/MCA with various array platforms, we detected 22 individuals (14 index patients and 8 family members) with deletions in 16p11.2, which are genomically identical to those identified in the autism studies. Though some patients shared a facial resemblance and a tendency to overweight, there was no evidence for a recognizable phenotype. Autism was not the presenting feature in our series. The assembled evidence indicates that recurrent 16p11.2 deletions are associated with variable clinical outcome, most likely arising from haploinsufficiency of one or more genes. The phenotypical spectrum ranges from MR and/or MCA, autism, learning and speech problems, to a normal phenotype.
Assuntos
Transtorno Autístico/genética , Deleção Cromossômica , Cromossomos Humanos Par 16 , Deficiência Intelectual/genética , Anormalidades Múltiplas , Adolescente , Adulto , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Análise Mutacional de DNA , Saúde da Família , Feminino , Testes Genéticos , Humanos , Lactente , Deficiências da Aprendizagem , Masculino , Distúrbios da Fala , Adulto JovemRESUMO
BACKGROUND: The Wolf-Hirschhorn syndrome (WHS) is usually caused by terminal deletions of the short arm of chromosome 4 and is phenotypically defined by growth and mental retardation, seizures, and specific craniofacial manifestations. Large variation is observed in phenotypic expression of these features. In order to compare the phenotype with the genotype, we localised the breakpoints of the 4 pter aberrations using a chromosome 4 specific tiling BAC/PAC array. METHODS: In total, DNA from 21 patients was analysed, of which 8 had a cytogenetic visible and 13 a submicroscopic deletion. RESULTS AND CONCLUSION: In addition to classical terminal deletions sized between 1.9 and 30 Mb, we observed the smallest terminal deletion (1.4 Mb) ever reported in a patient with mild WHS stigmata. In addition, we identified and mapped interstitial deletions in four patients. This study positions the genes causing microcephaly, intrauterine and postnatal growth retardation between 0.3 and 1.4 Mb and further refines the regions causing congenital heart disease, cleft lip and/or palate, oligodontia, and hypospadias.
Assuntos
Cromossomos Humanos Par 4/genética , Síndrome de Wolf-Hirschhorn/genética , Criança , Quebra Cromossômica , Deleção Cromossômica , Cromossomos Artificiais Bacterianos/genética , Cromossomos Artificiais de Bacteriófago P1/genética , Feminino , Genótipo , Humanos , Hibridização in Situ Fluorescente , Masculino , Hibridização de Ácido Nucleico , FenótipoRESUMO
INTRODUCTION: The 22q13.3 deletion syndrome (MIM 606232) is characterised by neonatal hypotonia, normal to accelerated growth, absent to severely delayed speech, global developmental delay, and minor dysmorphic facial features. We report the molecular characterisation of the deletion breakpoint in two unrelated chromosome 22q13.3 deletion cases. METHODS: The deletions were characterised by FISH, checked for other abnormalities by array-CGH, and confirmed by Real-Time PCR, and finally the breakpoints were cloned, sequenced, and compared. RESULTS: Both cases show the cardinal features of the 22q13.3 deletion syndrome associated with a deletion involving the last 100 kb of chromosome 22q13.3. The cases show a breakpoint within the same 15 bp repeat unit, overlapping the results obtained by Wong and colleagues in 1997 and suggesting that a recurrent deletion breakpoint exists within the SHANK3 gene. The direct repeat involved in these 22q13 deletion cases is presumably able to form slipped (hairpin) structures, but it also has a strong potential for forming tetraplex structures. DISCUSSION: Three cases with a common breakpoint within SHANK3 share a number of common phenotypic features, such as mental retardation and developmental delay with severely delayed or absent expressive speech. The two cases presented here, having a deletion partially overlapping the commercial subtelomeric probe, highlight the difficulties in interpreting FISH results and suggest that many similar cases may be overlooked.
Assuntos
Proteínas de Transporte/genética , Quebra Cromossômica , Deleção Cromossômica , Cromossomos Humanos Par 22 , Anormalidades Múltiplas/genética , Adolescente , Sequência de Bases , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/genética , Dados de Sequência Molecular , Proteínas do Tecido Nervoso , Recidiva , Homologia de Sequência do Ácido Nucleico , SíndromeRESUMO
Chromosomal aberrations are a common cause of multiple anomaly syndromes that include growth and developmental delay and dysmorphism. Novel high resolution, whole genome technologies, such as array based comparative genomic hybridisation (array-CGH), improve the detection rate of submicroscopic chromosomal abnormalities allowing re-investigation of cases where conventional cytogenetic techniques, Spectral karyotyping (SKY), and FISH failed to detect abnormalities. We performed a high resolution genome-wide screening for submicroscopic chromosomal rearrangements using array-CGH on 41 children with idiopathic mental retardation (MR) and dysmorphic features. The commercially available microarray from Spectral Genomics contained 2600 BAC clones spaced at approximately 1 Mb intervals across the genome. Standard chromosome analysis (>450 bands per haploid genome) revealed no chromosomal rearrangements. In addition, multi-subtelomeric FISH screening in 30 cases and SKY in 11 patients did not detect any abnormality. Using array-CGH we detected chromosomal imbalances in four patients (9.8%) ranging in size from 2 to 14 Mb. Large scale copy number variations were frequently observed. Array-CGH has become an important tool for the detection of chromosome aberrations and has the potential to identify genes involved in developmental delay and dysmorphism. Moreover, the detection of genomic imbalances of clinical significance will increase knowledge of the human genome by performing genotype-phenotype correlation.
Assuntos
Aberrações Cromossômicas , Deficiência Intelectual/genética , Hibridização de Ácido Nucleico/métodos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Hibridização in Situ Fluorescente , Lactente , Cariotipagem , Masculino , FenótipoAssuntos
Aberrações Cromossômicas , Cromossomos Artificiais Bacterianos , Testes Genéticos/métodos , Genoma Humano , Análise de Sequência com Séries de Oligonucleotídeos/métodos , DNA Complementar/genética , Feminino , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Masculino , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Sensibilidade e EspecificidadeRESUMO
Dyschondrosteosis (DCO; also called Léri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
Assuntos
Estatura/genética , Genes Homeobox , Proteínas de Homeodomínio/genética , Osteocondrodisplasias/genética , Southern Blotting , Humanos , Hibridização in Situ Fluorescente , Fenótipo , Reação em Cadeia da Polimerase , Proteína de Homoeobox de Baixa Estatura , SíndromeRESUMO
Twelve patients with varying degrees of mosaicism for a supernumerary ring chromosome were studied. The ring chromosomes were characterized using microdissection in combination with degenerate nucleotide-primed polymerase chain reaction (PCR) and reverse painting (micro-FISH). This method made it possible to determine the chromosomal origin of the ring chromosomes in detail, and thus to compare the phenotypes of similar cases. Eleven of the marker chromosomes were derived from the most proximal part of 1p, 3p, 3q, 5p, 7q, 8p, 8q, 9p, 10p and 20p. One marker chromosome had a complex origin, including the proximal and the most distal part of 20q. Eight of the families were also investigated for uniparental disomy (UPD) using microsatellite analysis. One case with maternal UPD 9 was found in a child with a ring chromosome derived from chromosome 9, r(9)(p10p12).
Assuntos
Aberrações Cromossômicas , Cromossomos em Anel , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Bandeamento Cromossômico , Feminino , Doenças Fetais/genética , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Repetições de Microssatélites , Reação em Cadeia da Polimerase , GravidezRESUMO
We describe a 34-year-old healthy woman with isochromosomes for the short and long arm of chromosome 9 who was ascertained because of repeated spontaneous abortions. Molecular analysis demonstrated maternal uniparental isodisomy for the whole chromosome 9, thus the origin of the isochromosomes was maternal. Because the patient had a normal phenotype, the maternal isodisomy supports the previous assumption that there are no maternally imprinted genes on chromosome 9.