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2.
Hum Genet ; 138(5): 501-508, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30982136

RESUMO

There is currently no oversight for canine clinical genetic testing laboratories. We published an initial set of standards and guidelines with the goal of providing a basis for which canine testing laboratories could evaluate their quality assurance programs. To further those standards and guidelines, we have developed a checklist that can be used as a self-evaluation to identify gaps in their programs for continual quality improvement over time. Because there is currently no organization willing to oversee an external proficiency program, the checklist provides the first step toward an internal, self-assessment that can be used periodically to monitor improvements. In addition, we attempt to address concerns from the canine community regarding rare or private mutations, genetic screening using array-based technologies, non-peer reviewed tests that are being offered, and the clinical validity of certain mutations in particular breeds. Through coordination, conversation and hard work, the canine genetic testing community can strive to organize to improve testing and to provide more transparency to consumers and better outcomes for dogs.


Assuntos
Experimentação Animal/normas , Testes Genéticos/veterinária , Guias como Assunto , Controle de Qualidade , Animais , Lista de Checagem , Modelos Animais de Doenças , Cães , Técnicas de Diagnóstico Molecular/normas , Mutação/genética
3.
J Vet Diagn Invest ; 31(2): 276-279, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30661469

RESUMO

Canine inherited factor VII deficiency is a mild-to-moderate, inherited coagulopathy that affects several breeds of dog. We identified 2 polymorphisms near the disease-causing F7 gene mutation, one of which interfered with testing in several Beagles by causing allele dropout of the normal, wild-type allele. In the absence of an external proficiency program among veterinary genetic testing laboratories, implementation of an internal proficiency program, which requires 2 independent methods for genotyping dogs at any given locus, was further enhanced by ensuring minimally non-overlapping primer pairs between the 2 assays. After redesign of our clinical tests, all dogs were re-examined, and the correct genotypes were identified. These changes ensure higher accuracy in future testing of the F7 mutation.


Assuntos
Testes Diagnósticos de Rotina/veterinária , Doenças do Cão/diagnóstico , Deficiência do Fator VII/veterinária , Fator VII/genética , Testes Genéticos/veterinária , Ensaio de Proficiência Laboratorial/métodos , Polimorfismo Genético , Alelos , Animais , Sequência de Bases , Testes Diagnósticos de Rotina/métodos , Cães , Fator VII/análise , Deficiência do Fator VII/diagnóstico , Testes Genéticos/métodos , Genótipo
4.
Hum Genet ; 2018 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-30426199

RESUMO

This publication represents a proposed approach to quality standards and guidelines for canine clinical genetic testing laboratories. Currently, there are no guidelines for laboratories performing clinical testing on dogs. Thus, there is no consensus set of protocols that set the minimal standards of quality among these laboratories, potentially causing variable results between laboratories, inconsistencies in reporting, and the inability to share information that could impact testing among organizations. A minimal standard for quality in testing is needed as breeders use the information from genetic testing to make breeding choices and irreversible decisions regarding spay, neuter or euthanasia. Incorrect results can have significant impact on the health of the dogs being tested and on their subsequent progeny. Because of the potentially serious consequences of an incorrect result or incorrect interpretation, results should be reviewed by and reported by individuals who meet a minimum standard of qualifications. Quality guidelines for canine genetic testing laboratories should include not only the analytical phase, but also the preanalytical and postanalytical phases, as this document attempts to address.

5.
Cytogenet Genome Res ; 2018 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-30071510

RESUMO

Merle is a distinct coat color and pattern found in numerous species, including the domestic dog, characterized by patches of diluted eumelanin (black pigment) interspersed among areas of normal pigmentation. In dogs, this variegated pattern is caused by an insertion of a SINE element into the canine PMEL gene. Although variation in the length of the SINE insertion - due to a variable-length poly(A) tail - has been observed to be associated with variation in merle coat color and patterning, no systematic evaluation of this correlation has been conducted and published in the scientific literature. We performed high-resolution analysis of the SINE insertion lengths in 175 dogs (99 Australian shepherds, 45 miniature Australian shepherds, and 31 miniature American shepherds) and compared the genotypes with the coat phenotypes (when available). SINE insertion lengths varied from 201 to 277 bp, indicating that merle insertion variants can occur in virtually any size along the entire continuum. Genotype-phenotype correlation of 126 dogs with only a single SINE insertion (m/M) identified at least 4 major phenotypic clusters designated as "cryptic," "atypical," "classic," and "harlequin" merle. However, we found several phenotypic outliers that did not cluster within these major groupings, suggesting that insertion size is not the only factor responsible for merle phenotypic variability. In addition, we detected 25 dogs with 2 SINE insertions (M/M) and 24 dogs with more than 2 PMEL (merle) alleles, indicating mosaicism. Genotype-phenotype correlation of M/M dogs suggests that cryptic merle alleles often act like non-merle (m) alleles when combined with atypical, classic, and harlequin-sized alleles. The finding of mosaicism has important implications for the dog's phenotype and the ability to potentially transmit various alleles to its offspring. Furthermore, we identified examples of the SINE insertion poly(A)-tail expansion and contraction between generations, which also has important implications for breeding practices and determining mating pairs to avoid producing double merle dogs. These data demonstrate that there is a continuum of merle insertion lengths associated with a spectrum of coat color and patterns and that genotype-phenotype exceptions and overlap make it difficult to strictly assign certain insertion sizes with an expected coat color, although some generalizations are possible.

6.
Am J Med Genet A ; 173(2): 395-406, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27759917

RESUMO

We performed whole-genome sequencing on an individual from a family with variable psychiatric phenotypes that had a sensory processing disorder, apraxia, and autism. The proband harbored a maternally inherited balanced translocation (46,XY,t(11;14)(p12;p12)mat) that disrupted LRRC4C, a member of the highly specialized netrin G family of axon guidance molecules. The proband also inherited a paternally derived chromosomal inversion that disrupted DPP6, a potassium channel interacting protein. Copy Number (CN) analysis in 14,077 cases with neurodevelopmental disorders and 8,960 control subjects revealed that 60% of cases with exonic deletions in LRRC4C had a second clinically recognizable syndrome associated with variable clinical phenotypes, including 16p11.2, 1q44, and 2q33.1 CN syndromes, suggesting LRRC4C deletion variants may be modifiers of neurodevelopmental disorders. In vitro, functional assessments modeling patient deletions in LRRC4C suggest a negative regulatory role of these exons found in the untranslated region of LRRC4C, which has a single, terminal coding exon. These data suggest that the proband's autism may be due to the inheritance of disruptions in both DPP6 and LRRC4C, and may highlight the importance of the netrin G family and potassium channel interacting molecules in neurodevelopmental disorders. © 2016 Wiley Periodicals, Inc.


Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Estudos de Associação Genética , Proteínas do Tecido Nervoso/genética , Transtornos do Neurodesenvolvimento/diagnóstico , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Canais de Potássio/genética , Receptores de Superfície Celular/genética , Regiões 5' não Traduzidas , Adolescente , Adulto , Apraxias/diagnóstico , Apraxias/genética , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Criança , Pré-Escolar , Pontos de Quebra do Cromossomo , Inversão Cromossômica , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cariótipo , Masculino , Pessoa de Meia-Idade , Família Multigênica , Linhagem , Translocação Genética , Adulto Jovem
7.
Cytogenet Genome Res ; 153(4): 198-204, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29421799

RESUMO

Genetic diseases occur in breeds used for law enforcement. As important team members, dogs are expected to operate at peak performance for several years and are significant investments for both the initial purchase and extensive, specialized training. Previous studies have not focused on causes for retirement or euthanasia as genetic (inherited) versus acquired (environmental). We performed direct mutational analysis for breed-specific conditions on samples from 304 dogs including 267 law enforcement (122 US, 87 Israeli, and 58 Polish) and 37 search and rescue dogs. Genetic testing identified 29% (n = 89) of the dogs tested to be carriers of a genetic mutation and 6% (n = 19) to be at risk for a debilitating inherited condition that may eventually impair the dog's ability to work. At-risk dogs included Labrador Retrievers (n = 4) with exercise-induced collapse, Bloodhounds (n = 2) with degenerative myelopathy (DM), and German Shepherd dogs with DM (n = 12) or leukocyte adhesion deficiency, type III (n = 1). A substantial number of working dogs were shown to be at risk for genetic conditions that may shorten the dog's career. The loss of dogs, due to early retirement or euthanasia, as a result of preventable genetic conditions has an emotional cost to handlers and financial cost to service organizations that can be avoided with genetic screening prior to breeding, buying, or training.


Assuntos
Doenças do Cão/epidemiologia , Cães/genética , Doenças Genéticas Inatas/veterinária , Animais , Cruzamento , Doenças do Cão/genética , Triagem de Portadores Genéticos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genótipo , Inquéritos Epidemiológicos , Israel/epidemiologia , Polônia/epidemiologia , Especificidade da Espécie , Estados Unidos/epidemiologia
8.
Am J Med Genet A ; 167A(2): 345-53, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25756153

RESUMO

Uniparental disomy (UPD) for imprinted chromosomes can cause abnormal phenotypes due to absent or overexpression of imprinted genes. UPD(14)pat causes a unique constellation of features including thoracic skeletal anomalies, polyhydramnios, placentomegaly, and limited survival; its hypothesized cause is overexpression of paternally expressed RTL1, due to absent regulatory effects of maternally expressed RTL1as. UPD(14)mat causes a milder condition with hypotonia, growth failure, and precocious puberty; its hypothesized cause is absence of paternally expressed DLK1. To more clearly establish how gains and losses of imprinted genes can cause disease, we report six individuals with copy number variations of the imprinted 14q32 region identified through clinical microarray-based comparative genomic hybridization. Three individuals presented with UPD(14)mat-like phenotypes (Temple syndrome) and had apparently de novo deletions spanning the imprinted region, including DLK1. One of these deletions was shown to be on the paternal chromosome. Two individuals with UPD(14)pat-like phenotypes had 122-154kb deletions on their maternal chromosomes that included RTL1as but not the differentially methylated regions that regulate imprinted gene expression, providing further support for RTL1 overexpression as a cause for the UPD(14)pat phenotype. The sixth individual is tetrasomic for a 1.7Mb segment, including the imprinted region, and presents with intellectual disability and seizures but lacks significant phenotypic overlap with either UPD(14) syndrome. Therefore, the 14q32 imprinted region is dosage sensitive, with deletions of different critical regions causing UPD(14)mat- and UPD(14)pat-like phenotypes, while copy gains are likely insufficient to recapitulate these phenotypes.


Assuntos
Cromossomos Humanos Par 14 , Variações do Número de Cópias de DNA , Estudos de Associação Genética , Família Multigênica , Fenótipo , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Duplicação Cromossômica , Hibridização Genômica Comparativa , Facies , Feminino , Loci Gênicos , Impressão Genômica , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Dissomia Uniparental , Adulto Jovem
9.
Eur J Hum Genet ; 23(2): 173-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24824130

RESUMO

Genomic copy-number variations (CNVs) constitute an important cause of epilepsies and other human neurological disorders. Recent advancement of technologies integrating genome-wide CNV mapping and sequencing is rapidly expanding the molecular field of pediatric neurodevelopmental disorders. In a previous study, a novel epilepsy locus was identified on 6q16.3q22.31 by linkage analysis in a large pedigree. Subsequent array comparative genomic hybridization (array CGH) analysis of four unrelated cases narrowed this region to ∼5 Mb on 6q22.1q22.31. We sought to further narrow the critical region on chromosome 6q22. Array CGH analysis was used in genome-wide screen for CNVs of a large cohort of patients with neurological abnormalities. Long-range PCR and DNA sequencing were applied to precisely map chromosomal deletion breakpoints. Finally, real-time qPCR was used to estimate relative expression in the brain of the candidate genes. We identified six unrelated patients with overlapping microdeletions within 6q22.1q22.31 region, three of whom manifested seizures. Deletions were found to be de novo in 5/6 cases, including all subjects presenting with seizures. We sequenced the deletion breakpoints in four patients and narrowed the critical region to a ∼250-kb segment at 6q22.1 that includes NUS1, several expressed sequence tags (ESTs) that are highly expressed in the brain, and putative regulatory sequences of SLC35F1. Our findings indicate that dosage alteration in particular, of NUS1, EST AI858607, or SLC35F1 are important contributors to the neurodevelopmental phenotype associated with 6q22 deletion, including epilepsy and tremors.


Assuntos
Cromossomos Humanos Par 6/genética , Epilepsia/genética , Deleção de Genes , Proteínas de Membrana Transportadoras/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Pré-Escolar , Epilepsia/diagnóstico , Feminino , Humanos , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas do Tecido Nervoso/genética , Receptores de Superfície Celular/genética
10.
Nat Genet ; 46(12): 1293-302, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25326701

RESUMO

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates. We discovered five structural configurations of the human chromosome 15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of segmental duplications and two independent inversion events. All inversion breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome 15 repeat that became organized into larger palindromic structures. GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3 microdeletions, the expansion of chromosome 15 segmental duplications in the human lineage and independent structural changes in apes. The significant clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role of this core duplicon and its palindromic architecture in promoting the evolutionary and disease-related instability of chromosome 15.


Assuntos
Transtornos Cromossômicos/genética , Deficiência Intelectual/genética , Sequências Repetitivas de Ácido Nucleico , Duplicações Segmentares Genômicas , Convulsões/genética , Animais , Evolução Biológica , Deleção Cromossômica , Cromossomos Artificiais Bacterianos , Cromossomos Humanos Par 15/genética , Análise por Conglomerados , Hibridização Genômica Comparativa , Dosagem de Genes , Genoma Humano , Humanos , Hibridização in Situ Fluorescente , Modelos Genéticos , Polimorfismo Genético , Primatas , Análise de Sequência de DNA
11.
Am J Hum Genet ; 95(5): 490-508, 2014 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-25307298

RESUMO

Neurodevelopmental disorders (NDDs) are caused by mutations in diverse genes involved in different cellular functions, although there can be crosstalk, or convergence, between molecular pathways affected by different NDDs. To assess molecular convergence, we generated human neural progenitor cell models of 9q34 deletion syndrome, caused by haploinsufficiency of EHMT1, and 18q21 deletion syndrome, caused by haploinsufficiency of TCF4. Using next-generation RNA sequencing, methylation sequencing, chromatin immunoprecipitation sequencing, and whole-genome miRNA analysis, we identified several levels of convergence. We found mRNA and miRNA expression patterns that were more characteristic of differentiating cells than of proliferating cells, and we identified CpG clusters that had similar methylation states in both models of reduced gene dosage. There was significant overlap of gene targets of TCF4 and EHMT1, whereby 8.3% of TCF4 gene targets and 4.2% of EHMT1 gene targets were identical. These data suggest that 18q21 and 9q34 deletion syndromes show significant molecular convergence but distinct expression and methylation profiles. Common intersection points might highlight the most salient features of disease and provide avenues for similar treatments for NDDs caused by different genetic mutations.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Transtornos Cromossômicos/genética , Anormalidades Craniofaciais/genética , Evolução Molecular , Haploinsuficiência/genética , Cardiopatias Congênitas/genética , Histona-Lisina N-Metiltransferase/genética , Deficiência Intelectual/genética , Células-Tronco Neurais , Fatores de Transcrição/genética , Células Cultivadas , Imunoprecipitação da Cromatina , Deleção Cromossômica , Cromossomos Humanos Par 18/genética , Cromossomos Humanos Par 9/genética , Metilação de DNA , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , MicroRNAs/genética , Microscopia Confocal , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sequência de RNA , Fator de Transcrição 4
12.
J Hum Genet ; 59(12): 667-74, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25319850

RESUMO

Cumulative data obtained from two relatively large pedigrees of a unique reciprocal chromosomal translocation (RCT) t(1;11)(p36.22;q12.2) ascertained by three miscarriages (pedigree 1) and the birth of newborn with hydrocephalus and myelomeningocele (pedigree 2) were used to estimate recurrence risks for different pregnancy outcomes. Submicroscopic molecular characterization by fluorescent in situ hybridization (FISH) of RCT break points in representative carriers showed similar rearrangements in both families. Meiotic segregation patterns after sperm analysis by three-color FISH of one male carrier showed all possible outcomes resulting from 2:2 and 3:1 segregations. On the basis of empirical survival data, we suggest that only one form of chromosome imbalance resulting in monosomy 1p36.22→pter with trisomy 11q12.2→qter may be observed in progeny at birth. Segregation analysis of these pedigrees was performed by the indirect method of Stengel-Rutkowski and showed that probability rate for malformed child at birth due to an unbalanced karyotype was 3/48 (6.2±3.5%) after ascertainment correction. The risk for stillbirths/early neonatal deaths was -/48 (<1.1%) and for miscarriages was 17/48 (35.4±6.9%). However, the probability rate for children with a normal phenotype at birth was 28/48 (58.3±7.1%). The results obtained from this study may be used to determine the risks for the various pregnancy outcomes for carriers of t(1;11)(p36.22;q12.2) and can be used for genetic counseling of carriers of this rearrangement.


Assuntos
Aborto Habitual/genética , Hidrocefalia/genética , Meningomielocele/genética , Resultado da Gravidez , Translocação Genética/genética , Aborto Habitual/patologia , Adulto , Segregação de Cromossomos , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 11/genética , Feminino , Humanos , Hidrocefalia/patologia , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Meningomielocele/fisiopatologia , Linhagem , Gravidez , Espermatozoides/patologia
13.
Chromosome Res ; 22(4): 517-32, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25179263

RESUMO

Despite that Robertsonian translocations (ROBs) are the most common chromosomal rearrangements in humans (1/1000 individuals), an exact breakpoint and the molecular mechanisms leading to their formation are still not well known. This is partly due to the fact that Human Genome Project did not provide any map or sequence for the acrocentric short arms. The main aim of our studies was to narrow the breakpoints in de novo arising and in familial cases of the most frequently occurring ROBs, using eight, previously not tested clones derived from 21p. Our results from PCR and FISH analysis showed that only the clones CR382285, CR382287, and a small fragment of CR382332 are retained in the examined ROBs. Moreover, interphase FISH on monochromosomal hybrids verified the orientation of studied clones in relation to centromeres of chromosomes 14 and 21. Given our results, we propose localization of the breakpoints in or nearby to clone CR382332. Summarizing, our results allowed to narrow the region where the breakpoints are localized and demonstrated that their position could be the same in all common ROBs.


Assuntos
Centrômero/genética , Pontos de Quebra do Cromossomo , Cromossomos/genética , Translocação Genética/genética , Cromossomos Artificiais Bacterianos , DNA Satélite/genética , Humanos , Hibridização in Situ Fluorescente , Interfase , Cariotipagem
14.
Dis Markers ; 2014: 836082, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24839341

RESUMO

Monosomy 1p36 is considered the most common subtelomeric deletion syndrome in humans and it accounts for 0.5-0.7% of all the cases of idiopathic intellectual disability. The molecular diagnosis is often made by microarray-based comparative genomic hybridization (aCGH), which has the drawback of being a high-cost technique. However, patients with classic monosomy 1p36 share some typical clinical characteristics that, together with its common prevalence, justify the development of a less expensive, targeted diagnostic method. In this study, we developed a simple, rapid, and inexpensive real-time quantitative PCR (qPCR) assay for targeted diagnosis of monosomy 1p36, easily accessible for low-budget laboratories in developing countries. For this, we have chosen two target genes which are deleted in the majority of patients with monosomy 1p36: PRKCZ and SKI. In total, 39 patients previously diagnosed with monosomy 1p36 by aCGH, fluorescent in situ hybridization (FISH), and/or multiplex ligation-dependent probe amplification (MLPA) all tested positive on our qPCR assay. By simultaneously using these two genes we have been able to detect 1p36 deletions with 100% sensitivity and 100% specificity. We conclude that qPCR of PRKCZ and SKI is a fast and accurate diagnostic test for monosomy 1p36, costing less than 10 US dollars in reagent costs.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Reação em Cadeia da Polimerase em Tempo Real/economia , Análise Custo-Benefício , Feminino , Marcadores Genéticos , Humanos , Masculino , Técnicas de Diagnóstico Molecular/economia , Monossomia/diagnóstico
15.
PLoS Genet ; 10(1): e1004139, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24497845

RESUMO

Inverted duplications are a common type of copy number variation (CNV) in germline and somatic genomes. Large duplications that include many genes can lead to both neurodevelopmental phenotypes in children and gene amplifications in tumors. There are several models for inverted duplication formation, most of which include a dicentric chromosome intermediate followed by breakage-fusion-bridge (BFB) cycles, but the mechanisms that give rise to the inverted dicentric chromosome in most inverted duplications remain unknown. Here we have combined high-resolution array CGH, custom sequence capture, next-generation sequencing, and long-range PCR to analyze the breakpoints of 50 nonrecurrent inverted duplications in patients with intellectual disability, autism, and congenital anomalies. For half of the rearrangements in our study, we sequenced at least one breakpoint junction. Sequence analysis of breakpoint junctions reveals a normal-copy disomic spacer between inverted and non-inverted copies of the duplication. Further, short inverted sequences are present at the boundary of the disomic spacer and the inverted duplication. These data support a mechanism of inverted duplication formation whereby a chromosome with a double-strand break intrastrand pairs with itself to form a "fold-back" intermediate that, after DNA replication, produces a dicentric inverted chromosome with a disomic spacer corresponding to the site of the fold-back loop. This process can lead to inverted duplications adjacent to terminal deletions, inverted duplications juxtaposed to translocations, and inverted duplication ring chromosomes.


Assuntos
Transtorno Autístico/genética , Variações do Número de Cópias de DNA/genética , Deficiência Intelectual/genética , Duplicações Segmentares Genômicas/genética , Transtorno Autístico/patologia , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , Replicação do DNA/genética , Amplificação de Genes , Genoma Humano , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Deficiência Intelectual/patologia
17.
Eur J Hum Genet ; 22(1): 57-63, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23632792

RESUMO

Copy number variations associated with abnormal gene dosage have an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID) and autism. We hypothesize that the chromosome 2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or duplication results in altered gene dosage. We previously established the 2q23.1 microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications, thus establishing a complementary duplication syndrome. The observed phenotype includes ID, language impairments, infantile hypotonia and gross motor delay, behavioral problems, autistic features, dysmorphic facial features (pinnae anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and minor digital anomalies (fifth finger clinodactyly and large broad first toe). The microduplication size varies among all cases and ranges from 68 kb to 53.7 Mb, encompassing a region that includes MBD5, an important factor in methylation patterning and epigenetic regulation. We previously reported that haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion syndrome and that mutations in MBD5 are associated with autism. In this study, we demonstrate that MBD5 is the only gene in common among all duplication cases and that overexpression of MBD5 is likely responsible for the core clinical features present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that 2q23.1 duplication results in a slightly less severe phenotype than the reciprocal deletion. The features associated with a deletion, mutation or duplication of MBD5 and the gene expression changes observed support MBD5 as a dosage-sensitive gene critical for normal development.


Assuntos
Transtornos Globais do Desenvolvimento Infantil/genética , Proteínas de Ligação a DNA/genética , Deficiências do Desenvolvimento/genética , Trissomia/genética , Adolescente , Criança , Transtornos Globais do Desenvolvimento Infantil/etiologia , Transtornos Globais do Desenvolvimento Infantil/patologia , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 2/genética , Hibridização Genômica Comparativa , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/patologia , Epigênese Genética , Feminino , Dosagem de Genes , Humanos , Lactente , Masculino
18.
Am J Med Genet A ; 164A(1): 62-9, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24243649

RESUMO

A syndrome associated with 19q13.11 microdeletions has been proposed based on seven previous cases that displayed developmental delay, intellectual disability, speech disturbances, pre- and post-natal growth retardation, microcephaly, ectodermal dysplasia, and genital malformations in males. A 324-kb critical region was previously identified as the smallest region of overlap (SRO) for this syndrome. To further characterize this microdeletion syndrome, we present five patients with deletions within 19q12q13.12 identified using a whole-genome oligonucleotide microarray. Patients 1 and 2 possess deletions overlapping the SRO, and Patients 3-5 have deletions proximal to the SRO. Patients 1 and 2 share significant phenotypic overlap with previously reported cases, providing further definition of the 19q13.11 microdeletion syndrome phenotype, including the first presentation of ectrodactyly in the syndrome. Patients 3-5, whose features include developmental delay, growth retardation, and feeding problems, support the presence of dosage-sensitive genes outside the SRO that may contribute to the abnormal phenotypes observed in this syndrome. Multiple genotype-phenotype correlations outside the SRO are explored, including further validation of the deletion of WTIP as a candidate for male hypospadias observed in this syndrome. We postulate that unique patient-specific deletions within 19q12q13.1 may explain the phenotypic variability observed in this emerging contiguous gene deletion syndrome.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 19 , Fenótipo , Anormalidades Múltiplas/genética , Adolescente , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Facies , Feminino , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Humanos , Lactente , Masculino , Síndrome
20.
Acta Neuropathol Commun ; 1: 45, 2013 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-24252393

RESUMO

Monosomy 1p36 is the most common subtelomeric chromosomal deletion linked to mental retardation and seizures. Neuroimaging studies suggest that monosomy 1p36 is associated with brain malformations including polymicrogyria and nodular heterotopia, but the histopathology of these lesions is unknown. Here we present postmortem neuropathological findings from a 10 year-old girl with monosomy 1p36, who died of respiratory complications. The findings included micrencephaly, periventricular nodular heterotopia in occipitotemporal lobes, cortical dysgenesis resembling polymicrogyria in dorsolateral frontal lobes, hippocampal malrotation, callosal hypoplasia, superiorly rotated cerebellum with small vermis, and lumbosacral hydromyelia. The abnormal cortex exhibited "festooned" (undulating) supragranular layers, but no significant fusion of the molecular layer. Deletion mapping demonstrated single copy loss of a contiguous 1p36 terminal region encompassing many important neurodevelopmental genes, among them four HES genes implicated in regulating neural stem cell differentiation, and TP73, a monoallelically expressed gene. Our results suggest that brain and spinal malformations in monosomy 1p36 may be more extensive than previously recognized, and may depend on the parental origin of deleted genes. More broadly, our results suggest that specific genetic disorders may cause distinct forms of cortical dysgenesis.


Assuntos
Anormalidades Múltiplas , Encéfalo/anormalidades , Deleção Cromossômica , Cromossomos Humanos Par 1 , Medula Espinal/anormalidades , Criança , Evolução Fatal , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética
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