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1.
Eur J Med Genet ; 62(8): 103691, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31176769

RESUMO

Mutations in the chromatin regulator gene BRPF1 were recently associated with the Intellectual Developmental Disorder With Dysmorphic Facies And Ptosis (IDDDFP). Up till now, clinical data of 22 patients are reported. Besides intellectual disability (ID), ptosis and blepharophimosis are frequent findings, with refraction problems, amblyopia and strabism as other reported ophthalmological features. Animal studies indicate BRPF1 as an important mediator in brain development. However, only 5 of 22 previously reported patients show structural brain abnormalities. We report on an additional patient harboring a novel de novo nonsense mutation p.(Glu219*) in BRPF1. He presented with ID, bilateral iris colobomas, facial nerve palsy and severe hypoplasia of the corpus callosum. Our findings support previous findings of brain abnormalities in BRPF1-mutations and indicates coloboma and facial nerve palsy as possible additional features of IDDDFP syndrome.

2.
Am J Med Genet A ; 179(7): 1276-1286, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31124279

RESUMO

Lysine-specific demethylase 6B (KDM6B) demethylates trimethylated lysine-27 on histone H3. The methylation and demethylation of histone proteins affects gene expression during development. Pathogenic alterations in histone lysine methylation and demethylation genes have been associated with multiple neurodevelopmental disorders. We have identified a number of de novo alterations in the KDM6B gene via whole exome sequencing (WES) in a cohort of 12 unrelated patients with developmental delay, intellectual disability, dysmorphic facial features, and other clinical findings. Our findings will allow for further investigation in to the role of the KDM6B gene in human neurodevelopmental disorders.

3.
Eur J Hum Genet ; 27(7): 1033-1043, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30820038

RESUMO

Bicuspid aortic valve (BAV) is the most common congenital heart defect (CHD), affecting 1-2% of the population. BAV is associated with thoracic aortic aneurysms (TAAs). Deleterious copy number variations (CNVs) were found previously in up to 10% of CHD cases. This study aimed at unravelling the contribution of deleterious deletions or duplications in 95 unrelated BAV/TAA patients. Seven unique or rare CNVs were validated, harbouring protein-coding genes with a role in the cardiovascular system. Based on the presence of overlapping CNVs in patients with cardiovascular phenotypes in the DECIPHER database, the identification of similar CNVs in whole-exome sequencing data of 67 BAV/TAA patients and suggested topological domain involvement from Hi-C data, supportive evidence was obtained for two genes (DGCR6 and TBX20) of the seven initially validated CNVs. A rare variant burden analysis using next-generation sequencing data from 637 BAV/TAA patients was performed for these two candidate genes. This revealed a suggestive genetic role for TBX20 in BAV/TAA aetiology, further reinforced by segregation of a rare TBX20 variant with the phenotype within a BAV/TAA family. To conclude, our results do not confirm a significant contribution for deleterious CNVs in BAV/TAA as only one potentially pathogenic CNV (1.05%) was identified. We cannot exclude the possibility that BAV/TAA is occasionally attributed to causal CNVs though, or that certain CNVs act as genetic risk factors by creating a sensitised background for BAV/TAA. Finally, accumulative evidence for TBX20 involvement in BAV/TAA aetiology underlines the importance of this transcription factor in cardiovascular disease.

4.
Eur J Med Genet ; 61(4): 209-212, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29191496

RESUMO

The 22q11.2 deletion syndrome (22q11DS), the most common survivable human genetic deletion disorder, is caused by a hemizygous deletion of 30-40 contiguous genes on chromosome 22, many of which have not been well characterized. Clinical features seen in patients with this deletion, including intellectual disability, are not completely penetrant and vary in severity between patients, suggesting the involvement of variants elsewhere in the genome in the manifestation of the phenotype. Given that it is a relatively rare disorder (1/2000-6000 in humans), limited research has shed light into the contribution of these second-site variants to the developmental pathogenesis that underlies 22q11DS. As CNVs throughout the genome might constitute such a genetic risk factor for variability in the 22q11DS phenotypes such as intellectual disability, we sought to determine if the overall burden of rare CNVs in the genetic background influenced the phenotypic variability. We analyzed CNV and clinical data from 66 individuals with 22q11DS, and found that 77% (51/66) of individuals with the 22q11DS also carry additional rare CNVs (<0.1% frequency). We observed several trends between CNV burden and phenotype, including that the burden of large rare CNVs (>200 Kb in size) was significantly higher in 22q11DS individuals with intellectual disability than with normal IQ. Our analysis shows that rare CNVs may contribute to intellectual disability 22q11DS, and further analysis on larger 22q11DS cohorts should be performed to confirm this correlation.


Assuntos
Variações do Número de Cópias de DNA , Síndrome de DiGeorge/genética , Deficiência Intelectual/genética , Síndrome de DiGeorge/patologia , Humanos , Deficiência Intelectual/patologia
6.
Genet Med ; 19(4): 386-395, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27632686

RESUMO

PURPOSE: Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. METHODS: We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. RESULTS: We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-ß signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. CONCLUSION: In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-ß signaling.Genet Med 19 4, 386-395.


Assuntos
Aneurisma Dissecante/genética , Aneurisma da Aorta Torácica/genética , Biglicano/genética , Mutação , Aneurisma Dissecante/metabolismo , Aneurisma da Aorta Torácica/metabolismo , Biglicano/metabolismo , Células Cultivadas , Feminino , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Humanos , Masculino , Linhagem , Análise de Sequência de DNA/métodos , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo
7.
Gene ; 605: 92-98, 2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-27993705

RESUMO

Intellectual disability (ID) affects approximately 1-2% of the general population and is characterized by impaired cognitive abilities. ID is both clinically as well as genetically heterogeneous, up to 2000 genes are estimated to be involved in the emergence of the disease with various clinical presentations. For many genes, only a few patients have been reported and causality of some genes has been questioned upon the discovery of apparent loss-of-function mutations in healthy controls. Description of additional patients strengthens the evidence for the involvement of a gene in the disease and can clarify the clinical phenotype associated with mutations in a particular gene. Here, we present two large four-generation families with a total of 11 males affected with ID caused by mutations in ZNF711, thereby expanding the total number of families with ID and a ZNF711 mutation to four. Patients with mutations in ZNF711 all present with mild to moderate ID and poor speech accompanied by additional features in some patients, including autistic features and mild facial dysmorphisms, suggesting that ZNF711 mutations cause non-syndromic ID.


Assuntos
Transtornos da Articulação/genética , Transtorno do Espectro Autista/genética , Proteínas de Ligação a DNA/genética , Genes Ligados ao Cromossomo X , Predisposição Genética para Doença , Deficiência Intelectual/genética , Mutação , Adolescente , Adulto , Transtornos da Articulação/diagnóstico , Transtornos da Articulação/fisiopatologia , Transtorno do Espectro Autista/diagnóstico , Transtorno do Espectro Autista/fisiopatologia , Sequência de Bases , Criança , Exoma , Feminino , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Análise de Sequência de DNA , Índice de Gravidade de Doença
8.
Eur J Hum Genet ; 25(1): 43-51, 2016 01.
Artigo em Inglês | MEDLINE | ID: mdl-27804958

RESUMO

Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.


Assuntos
Nanismo/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Fatores de Processamento de RNA/genética , Proteínas Repressoras/genética , Adolescente , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 8/genética , Nanismo/fisiopatologia , Exoma/genética , Feminino , Mutação da Fase de Leitura , Cardiopatias Congênitas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Fenótipo , Processamento de RNA/genética
9.
Eur J Hum Genet ; 24(12): 1724-1729, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27406249

RESUMO

In approximately 20% of individuals with Kagami-Ogata syndrome (KOS14, MIM 608149), characterized by a bell-shaped thorax with coat-hanger configuration of the ribs, joint contractures, abdominal wall defects and polyhydramnios during the pregnancy, the syndrome is caused by a maternal deletion of the imprinted gene cluster in chromosome 14q32.2. Most deletions reported so far included one or both of the differentially methylated regions (DMRs) - DLK1/MEG3 IG-DMR and MEG3-DMR. We present two unrelated families with two affected siblings each, presenting with classical KOS14 due to maternally inherited microdeletions. Interestingly, all four patients have lived through to adulthood, even though mortality rates for patients with KOS14 due to a microdeletion are relatively high. In the first family, none of the DMRs is included in the deletion and the methylation status is identical to that of controls. Deletions that do not encompass the DMRs in this region are thus sufficient to elicit the full KOS14 phenotype. In the second family, a partially overlapping deletion including both DMRs and MEG3 was detected. In summary, we show that patients with KOS14 can live into adulthood, that causal deletions do not have to include the DMRs and that consequently a normal methylation pattern does not exclude KOS14.


Assuntos
Transtornos Cromossômicos/genética , RNA não Traduzido/genética , Deleção de Sequência , Dissomia Uniparental/genética , Transtornos Cromossômicos/diagnóstico , Cromossomos Humanos Par 14/genética , Humanos , Linhagem , Fenótipo , Síndrome , Dissomia Uniparental/diagnóstico
10.
Eur J Paediatr Neurol ; 20(3): 474-9, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26818157

RESUMO

BACKGROUND: Biallelic loss-of-function mutations of phospholipase C-ß1 (PLCB1) have been described in three children with an early onset epileptic encephalopathy (EE). In two of them a homozygous deletion of the promotor and first three coding exons was found. The third patient had an almost identical heterozygous deletion in combination with a heterozygous splice site variant. All patients had intractable epilepsy and a severe developmental delay. METHODS AND RESULTS: We present the case of a boy with an infantile EE starting at the age of four months with a fever induced status epilepticus, modified hypsarrhythmia and developmental regression. The epilepsy was reasonably controlled with corticoids and valproate whereupon generalized tonic-clonic seizures appeared only each 3-4 months. However, only a slow developmental progress was seen hereafter, resulting in a severe intellectual disability with absent speech, motor delay and autistic features. We identified a novel homozygous partial deletion of PLCB1, affecting exons 7-9. CONCLUSIONS: This report emphasizes the role of PLCB1 haploinsufficiency in severe EE. We demonstrate a phenotypic variability in patients with a PLCB1-associated EE. In addition, our findings underscore the importance of microarray analysis in all patients with an EE of unknown etiology.


Assuntos
Epilepsia/genética , Mutação/genética , Fosfolipase C beta/genética , Deficiências do Desenvolvimento/genética , Heterozigoto , Homozigoto , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Espasmos Infantis/genética
11.
Eur J Med Genet ; 58(10): 503-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26327614

RESUMO

Recurrent rearrangements of chromosome 1q21.1 that occur as a consequence of non-allelic homologous recombination (NAHR) show considerable variability in phenotypic expression and penetrance. Chromosome 1q21.1 deletions (OMIM 612474) have been associated with microcephaly, intellectual disability, autism, schizophrenia, cardiac abnormalities and cataracts. Phenotypic features in individuals with 1q21.1 duplications (OMIM 612475) include macrocephaly, learning difficulties, developmental delay, intellectual disability and mild dysmorphic features. Half of these patients show autistic behavior. For the first time, we describe five patients, including monozygotic twins, with a triplication of the 1q21.1 chromosomal segment. Facial features common to all patients include a high, broad forehead; a flat and broad nasal bridge; long, downslanted palpebral fissures and dysplastic, low-set ears. Likely associated features include macrocephaly and increased weight. We observed that the triplications arose through different mechanisms in the patients: it was de novo in one patient, inherited from a triplication carrier in two cases, while the father of the twins is a 1q21.1 duplication carrier. The de novo triplication contained copies of both maternal alleles, suggesting it was generated by a combination of inter- and intrachromosomal recombination.


Assuntos
Cromossomos Humanos Par 1/genética , Anormalidades Craniofaciais/genética , Megalencefalia/genética , Sobrepeso/genética , Trissomia , Criança , Pré-Escolar , Anormalidades Craniofaciais/diagnóstico , Feminino , Humanos , Lactente , Masculino , Megalencefalia/diagnóstico , Sobrepeso/diagnóstico , Síndrome , Gêmeos Monozigóticos/genética
13.
PLoS Genet ; 10(4): e1004242, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24763282

RESUMO

Folate-sensitive fragile sites (FSFS) are a rare cytogenetically visible subset of dynamic mutations. Of the eight molecularly characterized FSFS, four are associated with intellectual disability (ID). Cytogenetic expression results from CGG tri-nucleotide-repeat expansion mutation associated with local CpG hypermethylation and transcriptional silencing. The best studied is the FRAXA site in the FMR1 gene, where large expansions cause fragile X syndrome, the most common inherited ID syndrome. Here we studied three families with FRA2A expression at 2q11 associated with a wide spectrum of neurodevelopmental phenotypes. We identified a polymorphic CGG repeat in a conserved, brain-active alternative promoter of the AFF3 gene, an autosomal homolog of the X-linked AFF2/FMR2 gene: Expansion of the AFF2 CGG repeat causes FRAXE ID. We found that FRA2A-expressing individuals have mosaic expansions of the AFF3 CGG repeat in the range of several hundred repeat units. Moreover, bisulfite sequencing and pyrosequencing both suggest AFF3 promoter hypermethylation. cSNP-analysis demonstrates monoallelic expression of the AFF3 gene in FRA2A carriers thus predicting that FRA2A expression results in functional haploinsufficiency for AFF3 at least in a subset of tissues. By whole-mount in situ hybridization the mouse AFF3 ortholog shows strong regional expression in the developing brain, somites and limb buds in 9.5-12.5dpc mouse embryos. Our data suggest that there may be an association between FRA2A and a delay in the acquisition of motor and language skills in the families studied here. However, additional cases are required to firmly establish a causal relationship.


Assuntos
Antígeno 2 Relacionado a Fos/genética , Proteínas Nucleares/genética , Expansão das Repetições de Trinucleotídeos/genética , Alelos , Sítios Frágeis do Cromossomo/genética , Metilação de DNA/genética , Feminino , Expressão Gênica/genética , Humanos , Deficiência Intelectual/genética , Masculino , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética
14.
Autism Res ; 5(4): 277-81, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22689534

RESUMO

In a developmentally delayed girl with an autism spectrum disorder, Single nucleotide polymorphism (SNP) array analysis showed a de novo 280 kb deletion on chromosome 16q23.2 involving two genes, GAN and CMIP. Inactivating mutations in GAN cause the autosomal recessive disorder giant axonal neuropathy, not present in our patient. CMIP was recently implicated in the etiology of specific language impairment by genome-wide association analysis. It modulates phonological short-term memory and hence plays an important role in language acquisition. Overlaps of specific language impairment and autism have been debated in the literature regarding the phenotypical language profile as well as etiology. Our patient illustrates that haploinsufficiency of CMIP may contribute to autism spectrum disorders. Our finding further supports the existence of a genetic overlap in the etiology of specific language impairment and autism.


Assuntos
Proteínas de Transporte/genética , Transtornos Globais do Desenvolvimento Infantil/genética , Deleção Cromossômica , Cromossomos Humanos Par 16/genética , Deficiências do Desenvolvimento/genética , Haploinsuficiência/genética , Proteínas Adaptadoras de Transdução de Sinal , Transtornos Globais do Desenvolvimento Infantil/diagnóstico , Pré-Escolar , Proteínas do Citoesqueleto/genética , Deficiências do Desenvolvimento/diagnóstico , Éxons/genética , Feminino , Triagem de Portadores Genéticos , Humanos , Lactente , Recém-Nascido , Transtornos do Desenvolvimento da Linguagem/diagnóstico , Transtornos do Desenvolvimento da Linguagem/genética , Estudos Longitudinais , Polimorfismo de Nucleotídeo Único/genética
15.
Am J Hum Genet ; 90(6): 1071-8, 2012 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-22608712

RESUMO

Williams-Beuren syndrome is a rare contiguous gene syndrome, characterized by intellectual disability, facial dysmorphisms, connective-tissue abnormalities, cardiac defects, structural brain abnormalities, and transient infantile hypercalcemia. Genes lying telomeric to RFC2, including CLIP2, GTF2I and GTF2IRD1, are currently thought to be the most likely major contributors to the typical Williams syndrome cognitive profile, characterized by a better-than-expected auditory rote-memory ability, a relative sparing of language capabilities, and a severe visual-spatial constructive impairment. Atypical deletions in the region have helped to establish genotype-phenotype correlations. So far, however, hardly any deletions affecting only a single gene in the disease region have been described. We present here two healthy siblings with a pure, hemizygous deletion of CLIP2. A putative role in the cognitive and behavioral abnormalities seen in Williams-Beuren patients has been suggested for this gene on the basis of observations in a knock-out mouse model. The presented siblings did not show any of the clinical features associated with the syndrome. Cognitive testing showed an average IQ for both and no indication of the Williams syndrome cognitive profile. This shows that CLIP2 haploinsufficiency by itself does not lead to the physical or cognitive characteristics of the Williams-Beuren syndrome, nor does it lead to the Williams syndrome cognitive profile. Although contribution of CLIP2 to the phenotype cannot be excluded when it is deleted in combination with other genes, our results support the hypothesis that GTF2IRD1 and GTF2I are the main genes causing the cognitive defects associated with Williams-Beuren syndrome.


Assuntos
Proteínas Associadas aos Microtúbulos/genética , Síndrome de Williams/genética , Adolescente , Adulto , Sequência de Bases , Transtornos do Comportamento Infantil/genética , Transtornos Cognitivos/genética , Feminino , Deleção de Genes , Genótipo , Haploinsuficiência , Heterozigoto , Humanos , Deficiência Intelectual/genética , Linguagem , Masculino , Modelos Genéticos , Dados de Sequência Molecular , Proteínas Musculares/genética , Proteínas Nucleares/genética , Fenótipo , Irmãos , Transativadores/genética , Fatores de Transcrição TFII/genética
16.
Am J Med Genet A ; 155A(2): 343-8, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21271651

RESUMO

Microdeletions, either subtelomeric or interstitial, are responsible for the mental handicap in approximately 10-20% of all patients. Currently, Multiplex Ligation-dependent Probe Amplification (MLPA) is widely used to detect these small aberrations in a routine fashion. Although cost-effective, the throughput is low and the degree of multiplexing is limited to maximally 40-50 probes. Therefore, we developed an array-based MLPA method, with probes identified by unique tag sequences, allowing the simultaneous analysis of 180 probes in a single experiment thereby covering all known mental retardation loci with at least two probes. We screened 120 patients with idiopathic mental retardation. In this group we detected 6 aberrations giving a detection rate of 5%, consistent with similar studies. In addition we tested 293 patients with mental retardation who were negative for fragile X syndrome and commercially available subtelomeric MLPA. We found seven causative rearrangements in this group (detection rate of 2.4%) thereby illustrating the value of including probes for interstitial microdeletion syndromes and additional probes in the telomeric regions in targeted screening sets for mental retardation. Array-based MLPA may thus be a good candidate to develop probe sets that rapidly detect copy number changes of disease associated loci in the human genome. This method may become a valuable tool in a routine diagnostic setting as it is a fast, user-friendly and relatively low-cost technique providing straightforward results requiring only 125 ng of genomic DNA.


Assuntos
Algoritmos , Deleção Cromossômica , Deficiência Intelectual/genética , Análise em Microsséries/métodos , Primers do DNA/genética , Sondas de DNA/genética , Humanos , Hibridização in Situ Fluorescente
17.
BMC Bioinformatics ; 12: 4, 2011 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-21208430

RESUMO

BACKGROUND: Microarray technology allows the analysis of genomic aberrations at an ever increasing resolution, making functional interpretation of these vast amounts of data the main bottleneck in routine implementation of high resolution array platforms, and emphasising the need for a centralised and easy to use CNV data management and interpretation system. RESULTS: We present CNV-WebStore, an online platform to streamline the processing and downstream interpretation of microarray data in a clinical context, tailored towards but not limited to the Illumina BeadArray platform. Provided analysis tools include CNV analsyis, parent of origin and uniparental disomy detection. Interpretation tools include data visualisation, gene prioritisation, automated PubMed searching, linking data to several genome browsers and annotation of CNVs based on several public databases. Finally a module is provided for uniform reporting of results. CONCLUSION: CNV-WebStore is able to present copy number data in an intuitive way to both lab technicians and clinicians, making it a useful tool in daily clinical practice.


Assuntos
Sistemas de Gerenciamento de Base de Dados , Armazenamento e Recuperação da Informação/métodos , Internet , Análise de Sequência com Séries de Oligonucleotídeos , Humanos
18.
J Med Genet ; 47(5): 299-311, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20452996

RESUMO

BACKGROUND: Chromosome 17p13.3 contains extensive repetitive sequences and is a recognised region of genomic instability. Haploinsufficiency of PAFAH1B1 (encoding LIS1) causes either isolated lissencephaly sequence or Miller-Dieker syndrome, depending on the size of the deletion. More recently, both microdeletions and microduplications mapping to the Miller-Dieker syndrome telomeric critical region have been identified and associated with distinct but overlapping phenotypes. METHODS: Genome-wide microarray screening was performed on 7678 patients referred with unexplained learning difficulties and/or autism, with or without other congenital abnormalities. Eight and five unrelated individuals, respectively, were identified with microdeletions and microduplications in 17p13.3. RESULTS: Comparisons with six previously reported microdeletion cases identified a 258 kb critical region, encompassing six genes including CRK (encoding Crk) and YWHAE (encoding 14-3-3epsilon). Clinical features included growth retardation, facial dysmorphism and developmental delay. Notably, one individual with only subtle facial features and an interstitial deletion involving CRK but not YWHAE suggested that a genomic region spanning 109 kb, encompassing two genes (TUSC5 and YWHAE), is responsible for the main facial dysmorphism phenotype. Only the microduplication phenotype included autism. The microduplication minimal region of overlap for the new and previously reported cases spans 72 kb encompassing a single gene, YWHAE. These genomic rearrangements were not associated with low-copy repeats and are probably due to diverse molecular mechanisms. CONCLUSIONS: The authors further characterise the 17p13.3 microdeletion and microduplication phenotypic spectrum and describe a smaller critical genomic region allowing identification of candidate genes for the distinctive facial dysmorphism (microdeletions) and autism (microduplications) manifestations.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 17/genética , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/genética , Lisencefalia/genética , Adolescente , Encéfalo/anormalidades , Criança , Pré-Escolar , Deleção Cromossômica , Lissencefalias Clássicas e Heterotopias Subcorticais em Banda/patologia , Anormalidades Craniofaciais/genética , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Lisencefalia/patologia , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Duplicações Segmentares Genômicas
19.
Eur J Med Genet ; 52(2-3): 94-100, 2009 Mar-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19249392

RESUMO

Interstitial deletions of 7q11.23 cause Williams-Beuren syndrome, one of the best characterized microdeletion syndromes. The clinical phenotype associated with the reciprocal duplication however is not well defined, though speech delay is often mentioned. We present 14 new 7q11.23 patients with the reciprocal duplication of the Williams-Beuren syndrome critical region, nine familial and five de novo. These were identified by either array-based MLPA or by array-CGH/oligonucleotide analysis in a series of patients with idiopathic mental retardation with an estimated population frequency of 1:13,000-1:20,000. Variable speech delay is a constant finding in our patient group, confirming previous reports. Cognitive abilities range from normal to moderate mental retardation. The association with autism is present in five patients and in one father who also carries the duplication. There is an increased incidence of hypotonia and congenital anomalies: heart defects (PDA), diaphragmatic hernia, cryptorchidism and non-specific brain abnormalities on MRI. Specific dysmorphic features were noted in our patients, including a short philtrum, thin lips and straight eyebrows. Our patient collection demonstrates that the 7q11.23 microduplication not only causes language delay, but is also associated with congenital anomalies and a recognizable face.


Assuntos
Transtornos Cromossômicos/genética , Cromossomos Humanos Par 7 , Anormalidades Múltiplas/genética , Criança , Pré-Escolar , Deleção Cromossômica , Face/anormalidades , Saúde da Família , Feminino , Humanos , Lactente , Deficiência Intelectual/genética , Masculino , Fenótipo , Distúrbios da Fala/genética , Síndrome , Síndrome de Williams/genética
20.
Arch Iran Med ; 11(3): 330-4, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18426327

RESUMO

Hereditary vitamin D-resistant rickets type or vitamin D-dependent rickets type II is a genetically determined and rare autosomal recessive disorder, most often caused by mutations in the vitamin D receptor gene. It usually presents with rachitic changes not responsive to vitamin D treatment and the circulating levels of 1,25 (OH)2 vitamin D-3 are elevated, differentiating it from vitamin D-dependent rickets type I. Alopecia capitis or alopecia totalis is seen in some families with vitamin D-dependent rickets type II. This is usually associated with a more severe phenotype. In this report, we present the clinical findings on a family which exhibited the typical clinical features of hereditary vitamin D-resistant rickets in two siblings. In addition, molecular analysis of the vitamin D receptor gene was performed by sequencing all coding exons. The cardinal findings in the index patient were alopecia totalis, renal tubular acidosis, mild generalized aminoaciduria, refractory rickets, high alkaline phosphatase, and hyperparathyroidism. Other routine biochemical tests were within normal limits, but 1+ glycine was detected in his urine. Skin biopsy results were compatible with alopecia areata. A previous child with similar phenotype was reported to be deceased at the age of 32 months. Mutation analysis of the vitamin D receptor gene by direct sequencing analysis of all coding exons showed a homozygous c.122GA(p.Cys41Tyr) variant in exon 2 with several arguments pointing to a pathogenic effect. We should be aware of this very rare disease whenever we see a patient with refractory rickets and alopecia.


Assuntos
Raquitismo Hipofosfatêmico Familiar/genética , Mutação , Receptores de Calcitriol/genética , Alopecia em Áreas/genética , Pré-Escolar , Consanguinidade , Éxons , Feminino , Triagem de Portadores Genéticos , Glicina/urina , Humanos , Lactente , Irã (Geográfico) , Masculino , Linhagem , Análise de Sequência , Irmãos
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