RESUMEN
A phenotype is emerging for the proximal pair of G-dark bands in 11q (11q14.1 and q14.3) but not yet for the distal pair (11q22.1 and q22.3). A mother and daughter with the same directly transmitted 12.3-Mb interstitial deletion of 11q21q22.3 (GRCh37: 93,551,765-105,817,723) both had initial feeding difficulties and failure to thrive, speech delay, learning difficulties, and mild dysmorphism. Among 17 patients with overlapping deletions, developmental or speech delay, dysmorphism, hypotonia, intellectual disability or learning difficulties, short stature, and coloboma were each found in 2 or more. These results may provide the basis for a consistent phenotype for this region. Among the 53 deleted and additional breakpoint genes, CNTN5, YAP1, and GRI4 were the most likely candidates. Non-penetrance of haploinsufficient genes and dosage compensation among related genes may account for the normal cognition in the mother and variable phenotypes that can extend into the normal range.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 11/genética , Anomalías Múltiples/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Contactinas/genética , Femenino , Humanos , Fenotipo , Receptores AMPA/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
The direct transmission of microscopically visible unbalanced chromosome abnormalities (UBCAs) is rare and usually has phenotypic consequences. Here we report four families in which a normal phenotype was initially found in one or more family members. Each UBCA was interpreted with regard to overlapping examples and factors previously associated with transmitted imbalances including incidental ascertainment, low gene density, benign copy number variation (CNV) content, and gene relatedness. A 4.56 Mb deletion of 8p23.1-p23.2 was thought to be causal in the affected proband but showed incomplete penetrance in her mother and sibling (Family 1). Incomplete penetrance was also associated with a 10.88 Mb duplication of 13q21.31-q22.1 (Family 3) and dosage insensitivity with a 17.6 Mb deletion of 22pter-q11.21 (Family 4) that were both ascertained at prenatal diagnosis and each found in 4 unaffected family members. The 22pter-q11.21 deletion is part of a region with high benign CNV content and supports the mapping of cat eye syndrome to a 600 kb interval of 22q11.1-q11.21. Low gene densities of less than 2.0 genes/Mb were found in each of these three families but only after segmentally duplicated genes were excluded from the deletions of 8p and 22q. In contrast, gene density was average and variable expressivity associated with a 3.59 Mb duplication of 8p23.1 incidentally ascertained for paternal infertility (Family 2). Our results indicate that a greater degree of direct parental transmission, incomplete penetrance, and variable expression are features of both sub-microscopic CNVs and UBCAs with relatively low gene and high benign CNV content.
Asunto(s)
Aberraciones Cromosómicas , Trastornos de los Cromosomas/diagnóstico , Trastornos de los Cromosomas/genética , Variaciones en el Número de Copia de ADN , Expresión Génica , Penetrancia , Adolescente , Adulto , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Preescolar , Bandeo Cromosómico , Deleción Cromosómica , Cromosomas Humanos Par 13 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 8 , Familia , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The 8p23.1 duplication syndrome (8p23.1 DS) is a recurrent genomic condition with an estimated prevalence of 1 in 58,000. The core 3.68 Mb duplication contains 32 genes of which five are currently candidates for the phenotypic features. Here we describe four patients and five families with eight microduplications of 8p23.1 ranging from 187 to 1082 kb in size and one atypical duplication of 4 Mb. These indicate that a minimal region of overlap (MRO) in medial 8p23.1 can give rise to features of 8p23.1 DS including developmental delay, dysmorphism, macrocephaly and otitis media, but not congenital heart disease (CHD). This MRO spans 776 kb (chr8:10,167,881-10,943,836 hg19) and contains SOX7 and seven of the other 32 core 8p23.1 DS genes. In centromeric 8p23.1, microduplications including GATA4 can give rise to non-syndromic CHD but the clinical significance of two smaller centromeric microduplications without GATA4 was uncertain due to severe neurological profiles not usually found in 8p23.1 DS. The clinical significance of three further 8p23.1 microduplications was uncertain due to additional genetic factors without which the probands might not have come to medical attention. Variable expressivity was indicated by the almost entirely unaffected parents in all five families and the mildly affected sibling in one. Intronic interruptions of six genes by microduplication breakpoint intervals had no apparent additional clinical consequences. Our results suggest that 8p23.1 DS is an oligogenetic condition largely caused by the duplication and interactions of the SOX7 and GATA4 transcription factors.
Asunto(s)
Anomalías Múltiples/genética , Cromosomas Humanos Par 8/genética , Discapacidades del Desarrollo/genética , Duplicación de Gen/genética , Adolescente , Niño , Preescolar , Deleción Cromosómica , Femenino , Factor de Transcripción GATA4/genética , Cardiopatías Congénitas/genética , Humanos , Lactante , Recién Nacido , Masculino , SíndromeRESUMEN
The 8p23.1 duplication syndrome is a relatively rare genomic condition that has been confirmed with molecular cytogenetic methods in only 11 probands and five family members. Here, we describe another prenatal and five postnatal patients with de novo 8p23.1 duplications analyzed with oligonucleotide array comparative genomic hybridization (oaCGH). Of the common features, mild or moderate developmental delays and/or learning difficulties have been found in 11/12 postnatal probands, a variable degree of mild dysmorphism in 8/12 and congenital heart disease (CHD) in 4/5 prenatal and 3/12 postnatal probands. Behavioral problems, cleft lip and/or palate, macrocephaly, and seizures were confirmed as additional features among the new patients, and novel features included neonatal respiratory distress, attention deficit hyperactivity disorder (ADHD), ocular anomalies, balance problems, hypotonia, and hydrocele. The core duplication of 3.68 Mb contains 31 genes and microRNAs of which only GATA4, TNKS, SOX7, and XKR6 are likely to be dosage sensitive genes and MIR124-1 and MIR598 have been implicated in neurocognitive phenotypes. A combination of the duplication of GATA4, SOX7, and related genes may account for the variable penetrance of CHD. Two of the duplications were maternal and intrachromosomal in origin with maternal heterozygosity for the common inversion between the repeats in 8p23.1. These additional patients and the absence of the 8p23.1 duplications in published controls, indicate that the 8p23.1 duplication syndrome may now be considered a pathogenic copy number variation (pCNV) with an estimated population prevalence of 1 in 58,000.
Asunto(s)
Anomalías Múltiples/diagnóstico , Discapacidades del Desarrollo/diagnóstico , Discapacidades para el Aprendizaje/diagnóstico , Trisomía/diagnóstico , Cariotipo Anormal , Anomalías Múltiples/genética , Adulto , Niño , Cromosomas Humanos Par 8/genética , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Femenino , Humanos , Lactante , Discapacidades para el Aprendizaje/genética , Masculino , Síndrome , Trisomía/genéticaRESUMEN
The central portion of the short arm of chromosome 5 is unusual in that large, cytogenetically visible interstitial deletions segregate in families with and without phenotypic consequences. Here we present a family in which a transmitted interstitial deletion of 5p13.3 to 5p14.3 co-segregated with learning and/or behavioral difficulties in six family members. Facial dysmorphism was not striking but a father and daughter both had lacrimal fistulae. The deletion was 12.23 Mb in size (chr5:20,352,535-32,825,775) and contained fifteen known protein coding genes. Five of these (GOLPH3; MTMR12; ZFR; SUB1; and NPR3) and an ultra-conserved microRNA (hsa-miR-579) were present in an 883 kb candidate gene region in 5p13.3 that was deleted in the present family but not in previously reported overlapping benign deletions. Members of the cadherin precursor gene cluster, with brain specific expression, were deleted in both affected and benign deletion families. The candidate genes in 5p13.3 may be sufficient to account for the consistent presence or absence of phenotype in medial 5p deletions. However, we consider the possibility of position effects in which CDH6, and/or other cadherin genes, become penetrant when adjacent genes, or modifiers of gene expression, are also deleted. This could account for the absence of intellectual disability in benign deletions of the cadherin cluster, the cognitive phenotype in medial 5p deletion syndrome and the greater severity of intellectual disability in patients with cri-du-chat syndrome and deletions of 5p15 that extend into the region deleted in the present family.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 5/genética , Discapacidades para el Aprendizaje/genética , Penetrancia , Cariotipo Anormal , Cadherinas/genética , Niño , Preescolar , Síndrome del Maullido del Gato/genética , Femenino , Humanos , Masculino , Trastornos Mentales/genética , Familia de Multigenes , Linaje , Examen FísicoRESUMEN
Deletions of the distal 3q22.3 region encompassing the gene forkhead transcription factor FOXL2 (FOXL2) usually result in intellectual disability (ID) and the highly recognizable blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). We encountered three patients with molecularly defined interstitial deletions distal to the FOXL2 gene. They present with remarkably similar manifestations comprising variable ID, a coarse facial appearance, including prominent nose and eyebrows, hypogonadism and skin pigmentation abnormalities, and they share an approximately 8.8 Mb overlapping 3q24q25 deletion. Interestingly, one of the present patients was described previously in a clinical report with emphasis on her clinical similarity to the Wisconsin syndrome, suggesting that Wisconsin syndrome might be caused by a (micro) deletion within the 3q24q25 region.
Asunto(s)
Blefarofimosis/genética , Deleción Cromosómica , Cromosomas Humanos Par 3/genética , Factores de Transcripción Forkhead/genética , Discapacidad Intelectual/genética , Fenotipo , Adolescente , Blefarofimosis/patología , Femenino , Proteína Forkhead Box L2 , Humanos , Discapacidad Intelectual/patología , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido Simple/genética , SíndromeRESUMEN
Cytogenetically visible imbalances without phenotypic effect are still rare despite the extent of large-scale copy number variation in the normal population revealed by array CGH. Here we report on a phenotypically normal 30-year-old female with a de novo, cytogenetically visible, interstitial deletion of band 4q34. She was referred following three successive miscarriages, one of which was an intra-uterine death with subendocardial fibroelastosis and dilated cardiomyopathy. There was no other notable medical or family history, she was of normal intelligence and had no dysmorphic features. FISH and Array CGH with a customized 1 Mb BAC array showed that the deletion is a minimum of 9.3 and a maximum of 10.7 Mb in size, between approximately 173 Mb in 4q34.1 and approximately 182 Mb in 4q34.3. The deletion contains only 23 known coding genes giving a low average gene density of approximately 2 genes/Mb. This case further illustrates that (1) sizeable imbalances can be associated with apparent phenotypic normality, (2) gene density is a better guide to possible phenotypic consequences than aberration size, and (3) it is not always safe to assume that de novo imbalances will be causal.
Asunto(s)
Emparejamiento Base/genética , Deleción Cromosómica , Cromosomas Humanos Par 4/genética , Adulto , Niño , Bandeo Cromosómico , Rotura Cromosómica , Mapeo Cromosómico , Femenino , Humanos , Hibridación Fluorescente in Situ , Masculino , FenotipoRESUMEN
Trisomy and tetrasomy of distal chromosome 15q have rarely been reported. Although most of the described patients have some learning difficulties and are overgrown, the phenotype associated with distal trisomy/tetrasomy 15q is uncertain due to the small numbers of reported cases and the common co-occurrence of additional chromosome deletions in many patients with trisomy 15q. We present five individuals with overgrowth, learning difficulties and increased dosage of distal 15q. Partial trisomy 15q was identified in four of these cases. Two were generated through recombination of a parental pericentric inversion and two were generated through malsegregation of a maternal balanced 14;15 reciprocal translocation. In all four cases the trisomy can be considered "pure" as the 14p and 15p monosomies will exert no phenotypic effect. Partial tetrasomy 15q, as the result of an analphoid supernumerary chromosome derived from an inverted duplication of distal 15q, was identified in the fifth patient. In addition to the overgrowth and learning difficulties, all five had a characteristic facial appearance and three had renal anomalies. The gestalt consists of a long, thin face with a prominent chin and nose. Renal anomalies included renal agenesis, horseshoe kidney, and hydronephrosis. We provide further support for a distinct "15q overgrowth syndrome" caused by either trisomy or tetrasomy resulting in increased dosage of distal 15q. In addition we propose that renal anomalies and a distinctive facial appearance be considered major features of this condition.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 15 , Aneuploidia , Tamaño Corporal , Cara/anomalías , Salud de la Familia , Femenino , Dosificación de Gen , Humanos , Enfermedades Renales , Discapacidades para el Aprendizaje , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.
Asunto(s)
Anomalías Múltiples/genética , Aberraciones Cromosómicas , Cromosomas Humanos Par 8/genética , Adulto , Citogenética , Femenino , Dosificación de Gen , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , Biología Molecular , Hibridación de Ácido Nucleico , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , EmbarazoRESUMEN
Large-scale copy number variation that is cytogenetically visible in normal individuals has been described as euchromatic variation but needs to be distinguished from pathogenic euchromatic deletion or duplication. Here, we report eight patients (three families and two individuals) with interstitial deletions of 9q13-q21.12. Fluorescence in situ hybridisation with a large panel of BACs showed that all the deleted clones were from extensive tracts of segmentally duplicated euchromatin, copies of which map to both the long and short arms of chromosome 9. The variety of reasons for which these patients were ascertained, and the phenotypically normal parents, indicates that this is a novel euchromatic variant with no phenotypic effect. Further, four patients with classical euchromatic variants of 9q12/qh or 9p12 were also shown to have duplications or triplications of this segmentally duplicated material common to both 9p and 9q. The cytogenetic boundaries between the segmentally duplicated regions and flanking unique sequences were mapped to 9p13.1 in the short arm (BAC RP11-402N8 at 38.7 Mb) and to 9q21.12 in the long arm (BAC RP11-88I18 at 70.3 Mb). The BACs identified in this study should in future make it possible to differentiate between clinically significant deletions or duplications and euchromatic variants with no established phenotypic consequences.
Asunto(s)
Centrómero , Aberraciones Cromosómicas , Cromosomas Humanos Par 9 , Eucromatina/genética , Dosificación de Gen , Adolescente , Adulto , Niño , Cromosomas Artificiales Bacterianos , Análisis Citogenético , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , FenotipoRESUMEN
A novel transmitted 2-3 Mb deletion of 2q14.1-q14.2 was found in an affected boy from a consanguineous family with a possible diagnosis of PEHO syndrome (OMIM 260565). BAC FISH showed that the deletion included a minimum of 20 genes including the homeobox engrailed 1 gene (EN1). However, the same deletion was also found in his phenotypically normal father and brother (family 1). The phenotype of the proband may, therefore, have been coincidental to the deletion, a result of a recessive condition within or outside the deleted segment or possibly due to variable dosage compensation of EN1 by the paralogous EN2 gene at 7q36. BAC FISH also showed that this deletion overlapped with a previously reported transmitted deletion of 2q13-q14.1 that had no phenotypic consequences (family 2). The deleted regions contained a total of 32 genes and comprise the final 5.25 Mb of the ancestral chromosome 2B from which chromosome 2 was formed in man. These families provide further evidence that heterozygous deletions of regions of low gene density are compatible with a normal phenotype.
Asunto(s)
Cromosomas Humanos Par 2/genética , Cromosomas Humanos Par 7/genética , Compensación de Dosificación (Genética)/genética , Eliminación de Gen , Proteínas de Homeodominio/genética , Anomalías Múltiples/genética , Adolescente , Adulto , Femenino , Heterocigoto , Humanos , Lactante , Masculino , Fenotipo , SíndromeRESUMEN
Segmental aneuploidy usually has phenotypic consequences but unbalanced rearrangements without phenotypic consequences have also been reported. In particular, harmless deletions of G-dark bands 5p14 and 16q21 have each been found in more than one independent family. Here, we report two families that were ascertained at prenatal diagnosis and had similar overlapping deletions that removed most of the gene poor G-dark band 2p12. PCR mapping showed that the deletions had a minimum size of 6.1 and 6.9 Mb with at least 13 hemizygous loci including a cluster of six pancreatic islet-regenerating genes. These deletions had no apparent phenotypic consequences in eight family members. In contrast, a third family was ascertained through a child with Wilm's tumour; both the child and his mother had more proximal deletions, developmental delay and some dysmorphic features. The deletion had a minimum size of 5.7 Mb and extended into the gene-rich area of 2p11.2. These results are consistent with the idea that there may be segments of the genome that are consistently haplosufficient. The introduction of higher resolution methods of dosage analysis into diagnostic laboratories is already revealing more transmitted abnormalities of uncertain significance. As a result, published cases of transmitted imbalances have been collected as a guide to the possible significance of such findings in the future (see the 'Chromosome Anomaly Collection' at www.som.soton.ac.uk/research/geneticsdiv).
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 2/genética , Páncreas/fisiología , Regeneración/genética , Eliminación de Secuencia , Tumor de Wilms/genética , Adulto , Preescolar , Bandeo Cromosómico , Cromosomas Humanos Par 18/genética , Femenino , Humanos , Lactante , Cariotipificación , Masculino , Familia de Multigenes , Linaje , Fenotipo , Diagnóstico Prenatal , TrisomíaRESUMEN
It has been proposed that duplications of 8p23.1 are either euchromatic variants of the 8p23.1 defensin domain with no phenotypic consequences or true duplications associated with developmental delay and heart defects. Here, we provide evidence for both alternatives in two new families. A duplication of most of band 8p23.1 (circa 5 Mb) was found in a girl of 8 years with pulmonary stenosis and mild language delay. BAC fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) showed that the two copies of the duplicated segment were sited, in an alternating fashion, between three copies of a circa 300-450 kb segment from 8p23.1 distal to REPD. Copy number of the variable 8p23.1 defensin domain was consistent with duplication but within the normal range. Duplication of the GATA-binding protein 4 gene (GATA4) in this patient and others with and without heart defects, suggests it is a dosage-sensitive gene with variable penetrance. A cytogenetically similar duplication of 8p23.1 was found at prenatal diagnosis in a fetus, father and grandmother. There was no duplication using BAC FISH but MAPH showed 11 copies of the 360 kb variable defensin domain which is within the expanded range found in previous euchromatic variant carriers. Semiquantitative FISH (SQ-FISH) was consistent with a simultaneous expansion of the adjacent olfactory receptor repeats. These results distinguish duplications of 8p23.1 with clinically significant consequences from benign copy number variants, which have not yet been associated with qualitative or quantitative traits.
Asunto(s)
Aberraciones Cromosómicas , Cromosomas Humanos Par 8 , Proteínas de Unión al ADN/genética , Duplicación de Gen , Factores de Transcripción/genética , Niño , Defensinas/genética , Femenino , Factor de Transcripción GATA4 , Humanos , Hibridación Fluorescente in Situ , Lactante , Trastornos del Desarrollo del Lenguaje/genética , Masculino , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Estenosis de la Válvula Pulmonar/genéticaAsunto(s)
Aneuploidia , Inversión Cromosómica , Cromosomas Humanos Par 1/genética , Anomalías Craneofaciales/genética , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Femenino , Cardiopatías Congénitas/genética , Humanos , Hibridación Fluorescente in Situ , Lactante , Fenotipo , SíndromeRESUMEN
Chromosome 16 contains multiple copy number variations (CNVs) that predispose to genomic disorders. Here, we differentiate pathogenic duplications of 16p11.2-p12.2 from microscopically similar euchromatic variants of 16p11.2. Patient 1 was a girl of 18 with autism, moderate intellectual disability, behavioural difficulties, dysmorphic features and a 7.71-Mb (megabase pair) duplication (16:21 521 005-29 233 146). Patient 2 had a 7.81-Mb duplication (16:21 382 561-29 191 527), speech delay and obsessional behaviour as a boy and, as an adult, short stature, macrocephaly and mild dysmorphism. The duplications contain 65 coding genes of which Polo-like kinase 1 (PLK1) has the highest likelihood of being haploinsufficient and, by implication, a triplosensitive gene. An additional 1.11-Mb CNV of 10q11.21 in Patient 1 was a possible modifier containing the G-protein-regulated inducer of neurite growth 2 (GPRIN2) gene. In contrast, the euchromatic variants in Patients 3 and 4 were amplifications from a 945-kb region containing non-functional immunoglobulin heavy chain (IGHV), hect domain pseudogene (HERC2P4) and TP53-inducible target gene 3 (TP53TG3) loci in proximal 16p11.2 (16:31 953 353-32 898 635). Paralogous pyrosequencing gave a total copy number of 3-8 in controls and 8 to >10 in Patients 3 and 4. The 16p11.2-p12.2 duplication syndrome is a recurrent genomic disorder with a variable phenotype including developmental delay, dysmorphic features, mild to severe intellectual disability, autism, obsessive or stereotyped behaviour, short stature and anomalies of the hands and fingers. It is important to differentiate pathogenic 16p11.2-p12.2 duplications from harmless, microscopically similar euchromatic variants of proximal 16p11.2, especially at prenatal diagnosis.
Asunto(s)
Trastorno Autístico , Proteínas de Ciclo Celular , Duplicación Cromosómica/genética , Cromosomas Humanos Par 16/genética , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Anomalías Múltiples/genética , Anomalías Múltiples/fisiopatología , Adolescente , Adulto , Trastorno Autístico/genética , Trastorno Autístico/fisiopatología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Niño , Preescolar , Variaciones en el Número de Copia de ADN/genética , Discapacidades del Desarrollo/genética , Discapacidades del Desarrollo/fisiopatología , Femenino , Genoma Humano , Humanos , Lactante , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Trastornos del Desarrollo del Lenguaje/genética , Trastornos del Desarrollo del Lenguaje/fisiopatología , Masculino , Fenotipo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Quinasa Tipo Polo 1RESUMEN
Duplications of distal 8p with and without significant clinical phenotypes have been reported and are often associated with an unusual degree of structural complexity. Here, we present a duplication of 8p23.1-8p23.2 ascertained in a child with speech delay and a diagnosis of ICD-10 autism. The same duplication was found in his mother who had epilepsy and learning problems. A combination of cytogenetic, FISH, microsatellite, MLPA and oaCGH analysis was used to show that the duplication extended over a minimum of 6.8 Mb between 3 539 893 and 10 323 426 bp. This interval contains 32 novel and 41 known genes, of which only microcephalin (MCPH1) is a plausible candidate gene for autism at present. The distal breakpoint of the duplicated region interrupts the CSMD1 gene in 8p23.2 and the medial breakpoint lies between the MSRA and RP1L1 genes in 8p23.1.An interchromosomal insertion between a normal and polymorphically inverted chromosome 8 is proposed to explain the origin of this duplication. Further mapped imbalances of distal 8p are needed to determine whether the autistic component of the phenotype in this family results from the cumulative imbalance of many genes or dosage imbalance of an individual susceptibility gene.
Asunto(s)
Trastorno Autístico/genética , Cromosomas Humanos Par 8/genética , Duplicación de Gen , Trastornos del Desarrollo del Lenguaje/genética , Discapacidades para el Aprendizaje/genética , Adulto , Proteínas de Ciclo Celular , Preescolar , Mapeo Cromosómico , Proteínas del Citoesqueleto , Epilepsia/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Cariotipificación , Masculino , Madres , Mutagénesis Insercional , Proteínas del Tejido Nervioso/genética , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
Over the past four years, genome-wide studies have uncovered numerous examples of structural variation in the human genome. This includes structural variation that changes copy number, such as deletion and duplication, and structural variation that does not change copy number, such as orientation and positional polymorphism. One region that contains all these types of variation spans the chromosome band 8p23.1. This region has been studied in some depth, and the focus of this review is to examine our current understanding of the variation of this region. We also consider whether this region is a good model for other structurally variable regions in the genome and what the implications of this variation are for clinical studies. Finally, we discuss the bioinformatics challenges raised, discuss the evolution of the region, and suggest some future priorities for structural variation research.