RESUMO
The aim of this study was to determine the suitability of the comparative genomic hybridization to microarray (aCGH) technique for prenatal diagnosis, but also to assess the frequency of chromosomal aberrations that may lead to fetal malformations but are not included in the diagnostic report. We present the results of the aCGH in a cohort of 7400 prenatal cases, indicated for invasive testing due to ultrasound abnormalities, high-risk for serum screening, thickened nuchal translucency, family history of genetic abnormalities or congenital abnormalities, and advanced maternal age (AMA). The overall chromosomal aberration detection rate was 27.2% (2010/7400), including 71.2% (1431/2010) of numerical aberrations and 28.8% (579/2010) of structural aberrations. Additionally, the detection rate of clinically significant copy number variants (CNVs) was 6.8% (505/7400) and 0.7% (57/7400) for variants of unknown clinical significance. The detection rate of clinically significant submicroscopic CNVs was 7.9% (334/4204) for fetuses with structural anomalies, 5.4% (18/336) in AMA, 3.1% (22/713) in the group of abnormal serum screening and 6.1% (131/2147) in other indications. Using the aCGH method, it was possible to assess the frequency of pathogenic chromosomal aberrations, of likely pathogenic and of uncertain clinical significance, in the groups of cases with different indications for an invasive test.
Assuntos
Aberrações Cromossômicas , Feto , Hibridização Genômica Comparativa/métodos , Feminino , Feto/anormalidades , Humanos , Análise em Microsséries/métodos , Polônia , GravidezRESUMO
Congenital microcephaly causes smaller than average head circumference relative to age, sex and ethnicity and is most usually associated with a variety of neurodevelopmental disorders. The underlying etiology is highly heterogeneous and can be either environmental or genetic. Disruption of any one of multiple biological processes, such as those underlying neurogenesis, cell cycle and division, DNA repair or transcription regulation, can result in microcephaly. This etiological heterogeneity manifests in a clinical variability and presents a major diagnostic and therapeutic challenge, leaving an unacceptably large proportion of over half of microcephaly patients without molecular diagnosis. To elucidate the clinical and genetic landscapes of congenital microcephaly, we sequenced the exomes of 191 clinically diagnosed patients with microcephaly as one of the features. We established a molecular basis for microcephaly in 71 patients (37%), and detected novel variants in five high confidence candidate genes previously unassociated with this condition. We report a large number of patients with mutations in tubulin-related genes in our cohort as well as higher incidence of pathogenic mutations in MCPH genes. Our study expands the phenotypic and genetic landscape of microcephaly, facilitating differential clinical diagnoses for disorders associated with most commonly disrupted genes in our cohort.
Assuntos
Sequenciamento do Exoma/métodos , Redes Reguladoras de Genes , Microcefalia/genética , Mutação , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Linhagem , Análise de Sequência de DNARESUMO
Congenital heart defects (CHDs) appear in 8-10 out of 1000 live born newborns and are one of the most common causes of deaths. In fetuses, the congenital heart defects are found even 3-5 times more often. Currently, microarray comparative genomic hybridization (array CGH) is recommended by worldwide scientific organizations as a first-line test in the prenatal diagnosis of fetuses with sonographic abnormalities, especially cardiac defects. We present the results of the application of array CGH in 484 cases with prenatally diagnosed congenital heart diseases by fetal ultrasound scanning (256 isolated CHD and 228 CHD coexisting with other malformations). We identified pathogenic aberrations and likely pathogenic genetic loci for CHD in 165 fetuses and 9 copy number variants (CNVs) of unknown clinical significance. Prenatal array-CGH is a useful method allowing the identification of all unbalanced aberrations (number and structure) with a much higher resolution than the currently applied traditional assessment techniques karyotype. Due to this ability, we identified the etiology of heart defects in 37% of cases.
Assuntos
Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Cardiopatias Congênitas/diagnóstico , Diagnóstico Pré-Natal/métodos , Aberrações Cromossômicas , Feminino , Cardiopatias Congênitas/genética , Humanos , Gravidez , Sensibilidade e Especificidade , Ultrassonografia Pré-NatalRESUMO
KBG syndrome is a neurodevelopmental autosomal dominant disorder characterized by short stature, macrodontia, developmental delay, behavioral problems, speech delay and delayed closing of fontanels. Most patients with KBG syndrome are found to have a mutation in the ANKRD11 gene or a chromosomal rearrangement involving this gene. We hereby present clinical evaluations of 23 patients aged 4 months to 26 years manifesting clinical features of KBG syndrome. Mutation analysis in the patients was performed using panel or exome sequencing and array CGH. Besides possessing dysmorphic features typical of the KBG syndrome, nearly all patients had psychomotor hyperactivity (86%), 81% had delayed speech, 61% had poor weight gain, 56% had delayed closure of fontanel and 56% had a hoarse voice. Macrodontia and a height range of -1 SDs to -2 SDs were noted in about half of the patients; only two patients presented with short stature below -3 SDs. The fact that wide, delayed closing fontanels were observed in more than half of our patients with KBG syndrome confirms the role of the ANKRD11 gene in skull formation and suture fusion. This clinical feature could be key to the diagnosis of KBG syndrome, especially in young children. Hoarse voice is a previously undescribed phenotype of KBG syndrome and could further reinforce clinical diagnosis.
Assuntos
Anormalidades Múltiplas/genética , Doenças do Desenvolvimento Ósseo/genética , Deficiência Intelectual/genética , Proteínas Repressoras/genética , Anormalidades Dentárias/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Doenças do Desenvolvimento Ósseo/diagnóstico , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/fisiopatologia , Criança , Pré-Escolar , Aberrações Cromossômicas , Cromossomos Humanos Par 16/genética , Hibridização Genômica Comparativa , Nanismo/genética , Nanismo/fisiopatologia , Fácies , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Masculino , Mutação/genética , Fenótipo , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/diagnóstico por imagem , Anormalidades Dentárias/fisiopatologia , Sequenciamento do Exoma , Adulto JovemRESUMO
Mowat-Wilson syndrome is a rare neurodevelopmental disorder caused by pathogenic variants in the ZEB2 gene, intragenic deletions of the ZEB2 gene, and microdeletions in the critical chromosomal region 2q22-23, where the ZEB2 gene is located. Mowat-Wilson syndrome is characterized by typical facial features that change with the age, severe developmental delay with intellectual disability, and multiple congenital abnormalities. The authors describe the clinical and genetic aspects of 28th patients with Mowat-Wilson syndrome diagnosed in Poland. Characteristic dysmorphic features, psychomotor retardation, intellectual disability, and congenital anomalies were present in all cases. The incidence of most common congenital anomalies (heart defect, Hirschsprung disease, brain defects) was similar to presented in literature. Epilepsy was less common compared to previously reported cases. Although the spectrum of disorders in patients with Mowat-Wilson syndrome is wide, knowledge of characteristic dysmorphic features awareness of accompanying abnormalities, especially intellectual disability, improves detection of the syndrome.
Assuntos
Fácies , Doença de Hirschsprung , Deficiência Intelectual , Microcefalia , Doença de Hirschsprung/diagnóstico , Doença de Hirschsprung/genética , Humanos , Deficiência Intelectual/genética , Microcefalia/genética , Polônia , Homeobox 2 de Ligação a E-box com Dedos de Zinco/genéticaRESUMO
BACKGROUND: Mapping the breakpoints in de novo balanced chromosomal translocations (BCT) in symptomatic individuals provides a unique opportunity to identify in an unbiased way the likely causative genetic defect and thus find novel human disease candidate genes. Our aim was to fine-map breakpoints of de novo BCTs in a case series of nine patients. METHODS: Shallow whole-genome mate pair sequencing (SGMPS) together with long-range PCR and Sanger sequencing. In one case (BCT disrupting BAHD1 and RET) cDNA analysis was used to verify expression of a fusion transcript in cultured fibroblasts. RESULTS: In all nine probands 11 disrupted genes were found, that is, EFNA5, EBF3, LARGE, PPP2R5E, TXNDC5, ZNF423, NIPBL, BAHD1, RET, TRPS1 and SLC4A10. Five subjects had translocations that disrupted genes with so far unknown (EFNA5, BAHD1, PPP2R5E, TXNDC5) or poorly delineated impact on the phenotype (SLC4A10, two previous reports of BCT disrupting the gene). The four genes with no previous disease associations (EFNA5, BAHD1, PPP2R5E, TXNDC5), when compared with all human genes by a bootstrap test, had significantly higher pLI (p<0.017) and DOMINO (p<0.02) scores indicating enrichment in genes likely to be intolerant to single copy damage. Inspection of individual pLI and DOMINO scores, and local topologically associating domain structure suggested that EFNA5, BAHD1 and PPP2R5E were particularly good candidates for novel disease loci. The pathomechanism for BAHD1 may involve deregulation of expression due to fusion with RET promoter. CONCLUSION: SGMPS in symptomatic carriers of BCTs is a powerful approach to delineate novel human gene-disease associations.
Assuntos
Proteínas Cromossômicas não Histona/genética , Pontos de Quebra do Cromossomo , Transtornos Cromossômicos/genética , Efrina-A5/genética , Proteína Fosfatase 2/genética , Translocação Genética , Sequenciamento Completo do Genoma/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto JovemRESUMO
Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development.
Assuntos
Variações do Número de Cópias de DNA , Exoma , Malformações do Desenvolvimento Cortical/genética , Polimorfismo de Nucleotídeo Único , Caderinas/genética , Feminino , Heterogeneidade Genética , Humanos , Masculino , Malformações do Desenvolvimento Cortical/patologia , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genéticaRESUMO
FRMPD4 (FERM and PDZ Domain Containing 4) is a neural scaffolding protein that interacts with PSD-95 to positively regulate dendritic spine morphogenesis, and with mGluR1/5 and Homer to regulate mGluR1/5 signaling. We report the genetic and functional characterization of 4 FRMPD4 deleterious mutations that cause a new X-linked intellectual disability (ID) syndrome. These mutations were found to be associated with ID in ten affected male patients from four unrelated families, following an apparent X-linked mode of inheritance. Mutations include deletion of an entire coding exon, a nonsense mutation, a frame-shift mutation resulting in premature termination of translation, and a missense mutation involving a highly conserved amino acid residue neighboring FRMPD4-FERM domain. Clinical features of these patients consisted of moderate to severe ID, language delay and seizures alongside with behavioral and/or psychiatric disturbances. In-depth functional studies showed that a frame-shift mutation, FRMPD4p.Cys618ValfsX8, results in a disruption of FRMPD4 binding with PSD-95 and HOMER1, and a failure to increase spine density in transfected hippocampal neurons. Behavioral studies of frmpd4-KO mice identified hippocampus-dependent spatial learning and memory deficits in Morris Water Maze test. These findings point to an important role of FRMPD4 in normal cognitive development and function in humans and mice, and support the hypothesis that FRMPD4 mutations cause ID by disrupting dendritic spine morphogenesis in glutamatergic neurons.
Assuntos
Espinhas Dendríticas/metabolismo , Deficiência Intelectual/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Adolescente , Adulto , Idoso , Éxons/genética , Feminino , Mutação da Fase de Leitura/genética , Humanos , Masculino , Pessoa de Meia-Idade , Morfogênese/genética , Morfogênese/fisiologia , Mutação/genética , Neurogênese/genética , Neurogênese/fisiologia , Linhagem , Adulto JovemRESUMO
Due to its prevalence and its health-related, economic and social consequences, childhood and adult obesity is a complex, medical and civilizational problem, which has been on the increase in the last decade. The results of multi-center investigations reveal that genetic factors play an essential role in the etiopathogenesis of obesity, particularly in the case of extreme cases with very early onset. The Body Mass Index (BMI) is one of the most frequently used indicators of obesity and shows a strong genetic component with a 40-70% degree of heritability. The three types of genetically conditioned obesity are: (1) isolated (nonsyndromic) monogenic obesity, (2) syndromic monogenic obesity associated with dysmorphic features and/or congenital defects, caused by mutations in specific gene(s), (3) chromosomal aberrations, including submicroscopic changes. The most prevalent common (complex) obesity is linked to the presence of various changes in different genomic loci, which are subject to interactions and modifications by environmental (ethnic, dietary, lifestyle, bacterial flora, oxidative stress), as well as epigenetic (i.e., associated with DNA methylation, histone modification) and epistatic (gene-gene interaction) factors. Recent investigations using the modern methods of genome-wide association studies (GWAS), bioinformatics and proteomics, have made it possible to elucidate 8 key genes among the 97 genes most likely to play significant roles in the metabolic effects of obesity. The results of investigations on the pathogenesis of complex obesity do not as yet clarify the potential pathogenic significance of these genomic changes in humans. This article discusses the neuro-endocrinological regulation of the sensation of hunger and thirst, the clinical consequences of mutations in genes associated with the melanocortin pathway, and the features of the most common obesity syndromes, including syndromes conditioned by genomic imprinting. A diagnostic algorithm for cases of suspected syndromic obesity is proposed.
Assuntos
Predisposição Genética para Doença/genética , Obesidade/genética , Adulto , Criança , Epigenômica , Testes Genéticos , Humanos , Leptina/metabolismo , Obesidade/metabolismo , Obesidade Infantil , FenótipoRESUMO
Copy-number variants (CNVs) are an important cause of human neurodevelopmental disorders. We present the first case of a 424 kb de novo 20q13.11q13.12 microdeletion in a patient with attention deficit disorder, tics and autistic behaviors, such as emotional and behavioral problems, and movement stereotypes. This region includes three genes expressed in the brain: SFRS6, PTPRT and L3MBTL. Our results suggest that loss of the chromosomal region 20q13.11q13.12 is causative for the clinical findings observed in the patient.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 20 , Transtornos do Neurodesenvolvimento/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Adolescente , Proteínas Cromossômicas não Histona , Haploinsuficiência , Humanos , Masculino , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/patologia , Fosfoproteínas , Proteínas Repressoras , Fatores de Processamento de Serina-Arginina , Proteínas Supressoras de TumorRESUMO
Major congenital anomalies are detectable in 2-3 % of the newborn population. Some of their genetic causes are attributable to copy number variations identified by array comparative genomic hybridization (aCGH). The value of aCGH screening as a first-tier test in children with multiple congenital anomalies has been studied and consensus adopted. However, array resolution has not been agreed upon, specifically in the newborn or infant population. Moreover, most array studies have been focused on mixed populations of intellectual disability/developmental delay with or without multiple congenital anomalies, making it difficult to assess the value of microarrays in newborns. The aim of the study was to determine the optimal quality and clinical sensitivity of high-resolution array comparative genomic hybridization in neonates with multiple congenital anomalies. We investigated a group of 54 newborns with multiple congenital anomalies defined as two or more birth defects from more than one organ system. Cytogenetic studies were performed using OGT CytoSure 8 × 60 K microarray. We found ten rearrangements in ten newborns. Of these, one recurrent syndromic microduplication was observed, whereas all other changes were unique. Six rearrangements were definitely pathogenic, including one submicroscopic and five that could be seen on routine karyotype analysis. Four other copy number variants were likely pathogenic. The candidate genes that may explain the phenotype were discussed. In conclusion, high-resolution array comparative hybridization can be applied successfully in newborns with multiple congenital anomalies as the method detects a significant number of pathogenic changes, resulting in early diagnoses. We hypothesize that small changes previously considered benign or even inherited rearrangements should be classified as potentially pathogenic at least until a subsequent clinical assessment would exclude a developmental delay or dysmorphism.
Assuntos
Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Variações do Número de Cópias de DNA , Feminino , Humanos , Recém-Nascido , MasculinoRESUMO
Cleft lip with or without cleft palate is one of the most common birth defects of unknown etiology. A fraction of its genetic causes is attributable to copy number variations detected by array comparative genomic hybridization. The value of array comparative genomic hybridization screening as a first-tier test in the newborn population with multiple congenital anomalies has now been accepted. Due to unspecific clinical picture at this age, it can also be applied to neonates with isolated anomalies. Our purpose was to assess utility of array comparative genomic hybridization in the population of newborns with isolated cleft lip and palate. We conducted the study in a group of 52 Polish newborns with apparently isolated cleft lip and palate. In the study group, we found 8 rearrangements. Of these, 2 de novo events have been noted that potentially explain the phenotype. In addition, 2 novel candidate genes for cleft lip and palate, CHN2 and CDH19, are suggested. Given the high number of inherited potentially benign changes, we question the clinical utility of array comparative genomic hybridization in the newborn population with isolated cleft lip and palate, at the same time pointing to the need of skilled professional's clinical assessment at a later age. However, the value of this technology in searching for the cause of isolated anomalies cannot be underestimated.
Assuntos
Anormalidades Múltiplas/genética , Fenda Labial/genética , Fissura Palatina/genética , Hibridização Genômica Comparativa/estatística & dados numéricos , Caderinas/genética , Variações do Número de Cópias de DNA , Feminino , Rearranjo Gênico , Humanos , Recém-Nascido , Masculino , Fenótipo , PolôniaRESUMO
INTRODUCTION: Intellectual disability (ID)/Developmental delay (DD), which occurs in 1-3% of the population, accounts for a large number of cases regularly seen in genetics clinics. Currently, Array Comparative Genomic Hybridization (array CGH) is recommended by the International Standards for Cytogenomic Arrays (ISCA) Consortium as a first line test in the diagnostics of ID/DD, replacing G-banded chromosome analysis. THE AIM: Application of array CGH in clinical diagnostics of developmental delay/ intellectual disability in children. MATERIAL AND METHODS: We present the results of 8x60K oligonucleotide array application that was successfully implemented in a cohort of 112 patients with the clinical diagnosis of intellectual disability and accompanying dysmorphic features and/or congenital malformations. RESULTS: We have identified 37 copy number variants (CNVs) with the size ranging from 40 kb to numerical chromosomal aberrations, including unbalanced translocations and chromosome Y disomy, receiving an overall diagnostic yield of 33%. Known pathogenic changes were identified in 21.4% of the cases. Among patients with pathogenic CNVs identified by array CGH, 41.7% had a previously normal karyotype analysis. CONCLUSIONS: Our studies provide more insights into the benefits derived by using chromosomal microarray analysis and demonstrate the usefulness of array CGH as a first-tier clinical setting test in patients with intellectual disability.
Assuntos
Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Hibridização Genômica Comparativa/métodos , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/genética , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Adolescente , Adulto , Transtornos Dismórficos Corporais/diagnóstico , Transtornos Dismórficos Corporais/genética , Criança , Pré-Escolar , Aberrações Cromossômicas , Variações do Número de Cópias de DNA , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Adulto JovemRESUMO
The population frequencies of the CDKN2A common variants remain undetermined. In Poland, there is a common variant of the CDKN2A: an alanine to threonine substitution (A148T), which has been detected in other populations. We have recently showed that it is significantly overrepresented among Polish melanoma patients when compared to general population. Herein, we ascertained the prevalence of the A148T variant in 3,583 unselected cancer cases and 3,000 random control subjects from the same Polish population. We evaluated eleven different malignancies, representing the majority of all common cancer sites. Positive association with A148T variant was observed for lung cancer (OR, 2.0; p = 0.0052). A similar trend, although nonsignificant after the Bonferroni correction, was observed for colorectal cancer (OR, 1.5; p = 0.5499). These results suggest that A148T variant may be associated with a multi-organ cancer risk in the Polish population.
Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/genética , Genes p16 , Neoplasias/epidemiologia , Neoplasias/genética , Adulto , Idoso , Alanina , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/genética , Feminino , Variação Genética , Humanos , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polônia/epidemiologia , Prevalência , Medição de Risco , Fatores de Risco , TreoninaRESUMO
Both breast and lung cancers are common malignancies and within the context of known genetic predispositions to breast cancer, no association has been made in linking the two diseases together. This does not exclude the possibility that such associations may exist that lie outside the known high-risk breast cancer families. To examine the likelihood of common genetic factors that could influence the risk of disease, two sets of consecutively collected tumor groups were examined for the 3020insC mutation in the NOD2/CARD15 gene. A total of 4107 consecutively collected breast cancer patients were assessed for the prevalence of the 3020insC mutation and compared to a consecutively collected series of 389 lung cancer patients and 2068 control samples. The results revealed that a proportion of breast cancer patients who had a first or a second degree relative diagnosed with lung cancer were more likely to harbour a change in NOD2/CARD15 compared to patients who had no relatives affected by lung cancer. Furthermore, this difference appeared to be specific to the breast and lung cancer subgroup since there was no difference in the frequency of the 3020insC allele in the consecutively collected lung cancer patients. In conclusion, it appears that the 3020insC mutation of the NOD2/CARD15 gene may be a genetic predisposing factor for aggregations of breast and lung cancer.