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1.
Hum Genet ; 140(11): 1517-1523, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34599367

RESUMEN

Hair length can be a highly variable trait within the Felis catus species, varying between and within different cat breeds. Previous research has demonstrated this variability is due to recessive mutations within the fibroblast growth factor 5 (FGF5) gene. Following a genetic screen, four longhaired Maine Coons were identified that had only one copy of a known FGF5 mutation. We performed DNA sequencing on samples from two of these Maine Coons and identified a missense mutation in FGF5 c.577G > A p.Ala193Thr. Genetic screening via restriction digest was then performed on samples from the other two Maine Coons and an additional 273 cats of various breeds. This screening found that only the two additional Maine Coons were heterozygous for the novel variant. Furthermore, the novel variant was not identified after in silico analysis of 68 whole genome cat sequences from various breeds, demonstrating that this novel mutation is most likely a breed-specific variant for the Maine Coon, contributing to the longhair phenotype in about 3% of these cats.


Asunto(s)
Pelaje de Animal/anatomía & histología , Gatos/genética , Factor 5 de Crecimiento de Fibroblastos/genética , Mutación Missense , Animales , Gatos/anatomía & histología , Femenino , Factor 5 de Crecimiento de Fibroblastos/química , Heterocigoto , Masculino , Linaje
2.
Hum Genet ; 140(11): 1581-1591, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34370083

RESUMEN

One of the most unique coat color patterns in the domestic dog is merle (also known as dapple in the dachshund breed), characterized by patches of normal pigmentation surrounded by diluted eumelanin pigment. In dogs, this striking variegated pattern is caused by an insertion of a SINE element into the PMEL gene. Differences in the length of the SINE insertion [due to a variable-length poly(A)-tail] has been associated with variation in the merle coat color and patterning. We previously performed a systematic evaluation of merle in 175 Australian shepherds and related breeds and correlated the length of the merle insertion variants with four broad phenotypic clusters designated as "cryptic", "atypical", "classic", and "harlequin" merle. In this study, we evaluated the SINE insertions in 140 dachshunds and identified the same major merle phenotypic clusters with only slight variation between breeds. Specifically, we identified numerous cases of true "hidden" merle in dachshunds with light/red (pheomelanin) coats with little to no black/brown pigment (eumelanin) and thus minimal or no observable merle phenotype. In addition, we identified somatic and gonadal mosaicism, with one dog having a large insertion in the harlequin size range of M281 that had no merle phenotype and unintentionally produced a double merle puppy with anophthalmia. The frequent identification of cryptic, hidden, and mosaic merle variants, which can be undetectable by phenotypic inspection, should be of particular concern to breeders and illustrates the critical need for genetic testing for merle prior to breeding to avoid producing dogs with serious health problems.


Asunto(s)
Pelaje de Animal/anatomía & histología , Perros/genética , Pruebas Genéticas/veterinaria , Color del Cabello/genética , Antígeno gp100 del Melanoma/genética , Alelos , Animales , Cruzamiento , Perros/anatomía & histología , Femenino , Estudios de Asociación Genética , Genotipo , Masculino , Melaninas/genética , Mosaicismo , Mutación , Linaje , Fenotipo , Elementos de Nucleótido Esparcido Corto
3.
Hum Genet ; 140(11): 1619-1624, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34287710

RESUMEN

Microarray analysis is an efficient approach for screening and identifying cytogenetic imbalances in humans. SNP arrays, in particular, are a powerful way to identify copy-number gains and losses representing aneuploidy and aneusomy, but moreover, allow for the direct assessment of individual genotypes in known disease loci. Using these approaches, trisomies, monosomies, and mosaicism of whole chromosomes have been identified in human microarray studies. For canines, this approach is not widely used in clinical laboratory diagnostic practice. In our laboratory, we have implemented the use of a proprietary SNP array that represents approximately 650,000 loci across the domestic dog genome. During the validation of this microarray prior to clinical use, we identified three cases of aneuploidy after screening 2053 dogs of various breeds including monosomy X, trisomy X, and an apparent mosaic trisomy of canine chromosome 38 (CFA38). This study represents the first use of microarrays for copy-number evaluation to identify cytogenetic anomalies in canines. As microarray analysis becomes more routine in canine genetic testing, more cases of chromosome aneuploidy are likely to be uncovered.


Asunto(s)
Aneuploidia , Trastornos de los Cromosomas/veterinaria , Enfermedades de los Perros/genética , Perros/genética , Animales , Trastornos de los Cromosomas/genética , Cromosomas Humanos X/genética , Femenino , Masculino , Análisis por Micromatrices , Mosaicismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple , Aberraciones Cromosómicas Sexuales/veterinaria , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/genética , Trastornos de los Cromosomas Sexuales del Desarrollo Sexual/veterinaria , Trisomía/genética , Síndrome de Turner/genética , Síndrome de Turner/veterinaria
4.
Hum Genet ; 138(5): 501-508, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30982136

RESUMEN

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.


Asunto(s)
Experimentación Animal/normas , Pruebas Genéticas/veterinaria , Guías como Asunto , Control de Calidad , Animales , Lista de Verificación , Modelos Animales de Enfermedad , Perros , Técnicas de Diagnóstico Molecular/normas , Mutación/genética
5.
J Vet Diagn Invest ; 31(2): 276-279, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30661469

RESUMEN

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.


Asunto(s)
Pruebas Diagnósticas de Rutina/veterinaria , Enfermedades de los Perros/diagnóstico , Deficiencia del Factor VII/veterinaria , Factor VII/genética , Pruebas Genéticas/veterinaria , Ensayos de Aptitud de Laboratorios/métodos , Polimorfismo Genético , Alelos , Animales , Secuencia de Bases , Pruebas Diagnósticas de Rutina/métodos , Perros , Factor VII/análisis , Deficiencia del Factor VII/diagnóstico , Pruebas Genéticas/métodos , Genotipo
6.
Hum Genet ; 138(5): 493-499, 2019 May.
Artículo en Inglés | MEDLINE | ID: mdl-30426199

RESUMEN

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.


Asunto(s)
Experimentación Animal/normas , Pruebas Genéticas/veterinaria , Guías como Asunto , Control de Calidad , Animales , Modelos Animales de Enfermedad , Perros
7.
Cytogenet Genome Res ; 156(1): 22-34, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30071510

RESUMEN

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.

8.
Cytogenet Genome Res ; 153(4): 198-204, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29421799

RESUMEN

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.


Asunto(s)
Enfermedades de los Perros/epidemiología , Perros/genética , Enfermedades Genéticas Congénitas/veterinaria , Animales , Cruzamiento , Enfermedades de los Perros/genética , Tamización de Portadores Genéticos , Enfermedades Genéticas Congénitas/epidemiología , Enfermedades Genéticas Congénitas/genética , Predisposición Genética a la Enfermedad , Genotipo , Encuestas Epidemiológicas , Israel/epidemiología , Polonia/epidemiología , Especificidad de la Especie , Estados Unidos/epidemiología
9.
Am J Med Genet A ; 167A(2): 345-53, 2015 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-25756153

RESUMEN

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.


Asunto(s)
Cromosomas Humanos Par 14 , Variaciones en el Número de Copia de ADN , Estudios de Asociación Genética , Familia de Multigenes , Fenotipo , Adolescente , Adulto , Niño , Preescolar , Deleción Cromosómica , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Duplicación Cromosómica , Hibridación Genómica Comparativa , Facies , Femenino , Sitios Genéticos , Impresión Genómica , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Disomía Uniparental , Adulto Joven
10.
PLoS Genet ; 10(1): e1004139, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24497845

RESUMEN

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.


Asunto(s)
Trastorno Autístico/genética , Variaciones en el Número de Copia de ADN/genética , Discapacidad Intelectual/genética , Duplicaciones Segmentarias en el Genoma/genética , Trastorno Autístico/patología , Puntos de Rotura del Cromosoma , Hibridación Genómica Comparativa , Replicación del ADN/genética , Amplificación de Genes , Genoma Humano , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Discapacidad Intelectual/patología
11.
Am J Med Genet A ; 164A(1): 62-9, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-24243649

RESUMEN

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.


Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 19 , Fenotipo , Anomalías Múltiples/genética , Adolescente , Niño , Preescolar , Hibridación Genómica Comparativa , Facies , Femenino , Enfermedades Genéticas Congénitas/diagnóstico , Enfermedades Genéticas Congénitas/genética , Humanos , Lactante , Masculino , Síndrome
12.
Proc Natl Acad Sci U S A ; 110(37): 14990-4, 2013 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-23980137

RESUMEN

Obesity is a highly heritable condition and a risk factor for other diseases, including type 2 diabetes, cardiovascular disease, hypertension, and cancer. Recently, genomic copy number variation (CNV) has been implicated in cases of early onset obesity that may be comorbid with intellectual disability. Here, we describe a recurrent CNV that causes a syndrome associated with intellectual disability, seizures, macrocephaly, and obesity. This unbalanced chromosome translocation leads to duplication of over 100 genes on chromosome 12, including the obesity candidate gene G protein ß3 (GNB3). We generated a transgenic mouse model that carries an extra copy of GNB3, weighs significantly more than its wild-type littermates, and has excess intraabdominal fat accumulation. GNB3 is highly expressed in the brain, consistent with G-protein signaling involved in satiety and/or metabolism. These functional data connect GNB3 duplication and overexpression to elevated body mass index and provide evidence for a genetic syndrome caused by a recurrent CNV.


Asunto(s)
Duplicación de Gen , Proteínas de Unión al GTP Heterotriméricas/genética , Obesidad Infantil/genética , Adolescente , Adulto , Animales , Encéfalo/metabolismo , Niño , Preescolar , Deleción Cromosómica , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 8/genética , Modelos Animales de Enfermedad , Femenino , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP Heterotriméricas/metabolismo , Humanos , Masculino , Ratones , Ratones Transgénicos , Obesidad Infantil/metabolismo , Obesidad Infantil/patología , Linaje , Síndrome , Translocación Genética
13.
Am J Med Genet A ; 161A(4): 717-31, 2013 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-23495017

RESUMEN

Deletions at 2p16.3 involving exons of NRXN1 are associated with susceptibility for autism and schizophrenia, and similar deletions have been identified in individuals with developmental delay and dysmorphic features. We have identified 34 probands with exonic NRXN1 deletions following referral for clinical microarray-based comparative genomic hybridization. To more firmly establish the full phenotypic spectrum associated with exonic NRXN1 deletions, we report the clinical features of 27 individuals with NRXN1 deletions, who represent 23 of these 34 families. The frequency of exonic NRXN1 deletions among our postnatally diagnosed patients (0.11%) is significantly higher than the frequency among reported controls (0.02%; P = 6.08 × 10(-7) ), supporting a role for these deletions in the development of abnormal phenotypes. Generally, most individuals with NRXN1 exonic deletions have developmental delay (particularly speech), abnormal behaviors, and mild dysmorphic features. In our cohort, autism spectrum disorders were diagnosed in 43% (10/23), and 16% (4/25) had epilepsy. The presence of NRXN1 deletions in normal parents and siblings suggests reduced penetrance and/or variable expressivity, which may be influenced by genetic, environmental, and/or stochastic factors. The pathogenicity of these deletions may also be affected by the location of the deletion within the gene. Counseling should appropriately represent this spectrum of possibilities when discussing recurrence risks or expectations for a child found to have a deletion in NRXN1.


Asunto(s)
Moléculas de Adhesión Celular Neuronal/genética , Eliminación de Gen , Proteínas del Tejido Nervioso/genética , Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Trastorno Autístico/genética , Proteínas de Unión al Calcio , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Exones , Facies , Femenino , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , Persona de Mediana Edad , Moléculas de Adhesión de Célula Nerviosa , Penetrancia , Fenotipo , Esquizofrenia/genética , Adulto Joven
14.
Diagn Mol Pathol ; 22(1): 10-21, 2013 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23370423

RESUMEN

Acute promyelocytic leukemia (APL) is typically defined at the molecular level by a reciprocal translocation of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARA) genes. An accurate diagnosis of APL is critical for appropriate choice of therapy and prognostic assessment. Cryptic and variant rearrangements in APL are discoverable by a variety of molecular methods including fluorescence in situ hybridization (FISH), reverse transcriptase polymerase chain reaction, or gene sequencing. Rare reports of FISH-negative APL harboring cryptic rearrangements of PML-RARA detected by reverse transcriptase polymerase chain reaction or sequencing have been described. Here, we describe the detection of cryptic or variant PML-RARA rearrangements by translocation-based comparative genomic hybridization (tCGH), a recently described modification of traditional CGH technology that facilitates the detection of balanced translocations by means of the linear amplification of a potential translocation breakpoint region(s), in 2 unusual cases of APL. One tumor lacked detectable t(15;17) by karyotype and FISH, and the other tumor lacked the typical morphologic and immunophenotypic features of APL and had a variant 3-way translocation involving PML and RARA. PML-RARA translocations were identified by tCGH in both cases providing confirmation of the diagnosis of APL. These data emphasize the benefit of using complementary molecular methods including tCGH for detecting cryptic and variant PML-RARA translocations in unusual cases of APL.


Asunto(s)
Hibridación Genómica Comparativa/métodos , Reordenamiento Génico , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Proteínas Nucleares/genética , Patología Molecular/métodos , Receptores de Ácido Retinoico/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína de la Leucemia Promielocítica , Receptor alfa de Ácido Retinoico , Translocación Genética , Adulto Joven
15.
Methods Mol Biol ; 973: 69-85, 2013.
Artículo en Inglés | MEDLINE | ID: mdl-23412784

RESUMEN

Various microarray platforms, including BAC, oligonucleotide, and SNP arrays, have been shown to -provide clinically useful diagnostic and prognostic information for patients with myelodysplastic syndromes (MDS). Clinically useful arrays are designed with specific purposes in mind and with attention to genomic content and probe density. All array types have been shown to detect genomic copy gains and losses, with SNP arrays having the added advantage of detecting copy neutral loss of heterozygosity (CNLOH). The finding of CNLOH has led to the identification of certain disease genes implicated in the initiation or progression of myeloid diseases. In addition, SNP karyotyping alone, or in conjunction with routine cytogenetics, can affect the outcome prediction and improve prognostic stratification of patients with MDS. Patients who were reclassified after array testing as having adverse-risk chromosomal findings correlated with poor survival. Results of over 25 published studies support the use of arrays in MDS testing. Because few balanced translocations are found in MDS, this disease is particularly amenable to microarray testing, and studies have shown better disease classification, identification of cryptic changes, and prognostication in this heterogeneous group of disorders. Novel genomic alterations identified by array testing may lead to better targeted therapies for treating patients with MDS.


Asunto(s)
Hibridación Genómica Comparativa/métodos , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple , Animales , Hibridación Genómica Comparativa/instrumentación , Humanos , Síndromes Mielodisplásicos/diagnóstico , Análisis de Secuencia por Matrices de Oligonucleótidos/instrumentación , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos
16.
Neurogenetics ; 14(2): 99-111, 2013 May.
Artículo en Inglés | MEDLINE | ID: mdl-23389741

RESUMEN

MEF2C haploinsufficiency syndrome is an emerging neurodevelopmental disorder associated with intellectual disability, autistic features, epilepsy, and abnormal movements. We report 16 new patients with MEF2C haploinsufficiency, including the oldest reported patient with MEF2C deletion at 5q14.3. We detail the neurobehavioral phenotype, epilepsy, and abnormal movements, and compare our subjects with those previously reported in the literature. We also investigate Mef2c expression in the developing mouse forebrain. A spectrum of neurofunctional deficits emerges, with hyperkinesis a consistent finding. Epilepsy varied from absent to severe, and included intractable myoclonic seizures and infantile spasms. Subjects with partial MEF2C deletion were statistically less likely to have epilepsy. Finally, we confirm that Mef2c is present both in dorsal primary neuroblasts and ventral gamma-aminobutyric acid(GABA)ergic interneurons in the forebrain of the developing mouse. Given interactions with several key neurodevelopmental genes such as ARX, FMR1, MECP2, and TBR1, it appears that MEF2C plays a role in several developmental stages of both dorsal and ventral neuronal cell types.


Asunto(s)
Niño , Epilepsia/genética , Haploinsuficiencia/genética , Hipercinesia/genética , Interneuronas/metabolismo , Red Nerviosa/crecimiento & desarrollo , Adolescente , Adulto , Animales , Preescolar , Discapacidades del Desarrollo/genética , Femenino , Eliminación de Gen , Humanos , Lactante , Factores de Transcripción MEF2/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Fenotipo , Adulto Joven
17.
N Engl J Med ; 367(23): 2175-84, 2012 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-23215555

RESUMEN

BACKGROUND: Chromosomal microarray analysis has emerged as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. We aimed to evaluate the accuracy, efficacy, and incremental yield of chromosomal microarray analysis as compared with karyotyping for routine prenatal diagnosis. METHODS: Samples from women undergoing prenatal diagnosis at 29 centers were sent to a central karyotyping laboratory. Each sample was split in two; standard karyotyping was performed on one portion and the other was sent to one of four laboratories for chromosomal microarray. RESULTS: We enrolled a total of 4406 women. Indications for prenatal diagnosis were advanced maternal age (46.6%), abnormal result on Down's syndrome screening (18.8%), structural anomalies on ultrasonography (25.2%), and other indications (9.4%). In 4340 (98.8%) of the fetal samples, microarray analysis was successful; 87.9% of samples could be used without tissue culture. Microarray analysis of the 4282 nonmosaic samples identified all the aneuploidies and unbalanced rearrangements identified on karyotyping but did not identify balanced translocations and fetal triploidy. In samples with a normal karyotype, microarray analysis revealed clinically relevant deletions or duplications in 6.0% with a structural anomaly and in 1.7% of those whose indications were advanced maternal age or positive screening results. CONCLUSIONS: In the context of prenatal diagnostic testing, chromosomal microarray analysis identified additional, clinically significant cytogenetic information as compared with karyotyping and was equally efficacious in identifying aneuploidies and unbalanced rearrangements but did not identify balanced translocations and triploidies. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; ClinicalTrials.gov number, NCT01279733.).


Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Pruebas Genéticas/métodos , Cariotipificación , Análisis de Secuencia por Matrices de Oligonucleótidos , Diagnóstico Prenatal/métodos , Adulto , Cromosomas Humanos/genética , Síndrome de Down/diagnóstico , Femenino , Enfermedades Fetales/diagnóstico , Humanos , Cariotipo , Edad Materna , Embarazo , Ultrasonografía Prenatal
18.
N Engl J Med ; 367(14): 1321-31, 2012 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-22970919

RESUMEN

BACKGROUND: Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS: We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS: Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P=2.11×10(-38)). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P=0.02). CONCLUSIONS: Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.).


Asunto(s)
Anomalías Congénitas/genética , Variaciones en el Número de Copia de ADN , Discapacidades del Desarrollo/genética , Heterogeneidad Genética , Discapacidad Intelectual/genética , Fenotipo , Trastorno Autístico/genética , Niño , Hibridación Genómica Comparativa , Femenino , Genoma Humano , Humanos , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Factores Sexuales
19.
Prenat Diagn ; 32(10): 976-85, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22865506

RESUMEN

OBJECTIVE: To demonstrate the usefulness of microarray testing in prenatal diagnosis based on our laboratory experience. METHODS: Prenatal samples received from 2004 to 2011 for a variety of indications (n = 5003) were tested using comparative genomic hybridization-based microarrays targeted to known chromosomal syndromes with later versions of the microarrays providing backbone coverage of the entire genome. RESULTS: The overall detection rate of clinically significant copy number alterations (CNAs) among unbiased, nondemise cases was 5.3%. Detection rates were 6.5% and 8.2% for cases referred with abnormal ultrasounds and fetal demise, respectively. The overall rate of findings with unclear clinical significance was 4.2% but would reduce to 0.39% if only de novo CNAs were considered. In cases with known chromosomal rearrangements in the fetus or parent, 41.1% showed CNAs related to the rearrangements, whereas 1.3% showed clinically significant CNAs unrelated to the karyotype. Finally, 71% of the clinically significant CNAs found by microarray were below the resolution of conventional karyotyping of fetal chromosomes. CONCLUSIONS: Microarray analysis has advantages over conventional cytogenetics, including the ability to more precisely characterize CNAs associated with abnormal karyotypes. Moreover, a significant proportion of cases studied by array will show a clinically significant CNA even with apparently normal karyotypes.


Asunto(s)
Cariotipo Anormal/embriología , Hibridación Genómica Comparativa , Diagnóstico Prenatal/métodos , Aberraciones Cromosómicas/embriología , Femenino , Muerte Fetal/genética , Humanos , Cariotipificación/métodos , Análisis por Micromatrices/métodos , Embarazo , Estudios Prospectivos , Eliminación de Secuencia/genética , Ultrasonografía Prenatal
20.
Prenat Diagn ; 32(10): 986-95, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22847778

RESUMEN

OBJECTIVE: The aim of this study is to understand the diagnostic utility of comparative genomic hybridization (CGH)-based microarrays for pregnancies with abnormal ultrasound findings. METHODS: We performed a retrospective analysis of 2858 pregnancies with abnormal ultrasounds and normal karyotypes (when performed) tested in our laboratory using CGH microarrays targeted to known chromosomal syndromes with later versions providing backbone coverage of the entire genome. Abnormalities were stratified according to organ system involvement. Detection rates for clinically significant findings among these categories were calculated. RESULTS: Clinically significant genomic alterations were identified in cases with a single ultrasound anomaly (n = 99/1773, 5.6%), anomalies in two or more organ systems (n = 77/808, 9.5%), isolated growth abnormalities (n = 2/76, 2.6%), and soft markers (n = 2/77, 2.6%). The following anomalies in isolation or with additional anomalies had particularly high detection rates: holoprosencephaly (n = 9/85, 10.6%), posterior fossa defects (n = 21/144, 14.6%), skeletal anomalies (n = 15/140, 10.7%), ventricular septal defect (n = 14/132, 10.6%), hypoplastic left heart (n = 11/68, 16.2%), and cleft lip/palate (n = 14/136, 10.3%). CONCLUSIONS: Microarray analysis identified clinically significant genomic alterations in 6.5% of cases with one or more abnormal ultrasound findings; the majority were below the resolution of karyotyping. Larger data sets such as this allow for sub-stratification by specific anomalies to determine risks for genomic alterations detectable by microarray analysis.


Asunto(s)
Aberraciones Cromosómicas , Hibridación Genómica Comparativa , Anomalías Congénitas/diagnóstico por imagen , Análisis por Micromatrices/métodos , Diagnóstico Prenatal/métodos , Adulto , Huesos/anomalías , Encéfalo/anomalías , Anomalías Congénitas/genética , Femenino , Cardiopatías Congénitas/diagnóstico por imagen , Cardiopatías Congénitas/genética , Holoprosencefalia/diagnóstico por imagen , Holoprosencefalia/genética , Humanos , Cariotipificación , Mutación/genética , Embarazo , Estudios Retrospectivos , Ultrasonografía Prenatal
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