Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients

Borgatti, Renato; Piccinelli, Paolo; Passoni, Davide; Dalprà, Leda; Miozzo, Monica; Micheli, Roberto; Gagliardi, Chiara; Balottin, Umberto

doi:10.1016/s0887-8994(00)00244-7

Cited by 71 publications

(72 citation statements)

References 24 publications

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Section: E476mentioning

confidence: 91%

“…Several investigators have described a "chromosome 15 phenotype" in individuals with chromosome 15 duplications, characterized to variable degrees by ataxia, language delay, epilepsy, mental retardation, and facial dysmorphology. 101,103 The manifestations of this phenotype overlap with the autistic phenotype, giving credence to the involvement in ASD pathogenesis of a gene or genes in this region.The cytogenetic abnormalities of chromosome 15q11-q13 point to several gene targets for additional study. The ␥-amino butyric acid (GABA A ) receptor gene cluster (which contains genes for 3 of the receptor's subunits: GABRB3, GABRA5, and GABRG3) is strongly implicated in the pathogenesis of autism, given its involvement in the inhibition of excitatory neural pathways and its expression in early development.…”

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confidence: 91%

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The Genetics of Autism

2004

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ABSTRACT. Autism is a complex, behaviorally defined, static disorder of the immature brain that is of great concern to the practicing pediatrician because of an astonishing 556% reported increase in pediatric prevalence between 1991 and 1997, to a prevalence higher than that of spina bifida, cancer, or Down syndrome. This jump is probably attributable to heightened awareness and changing diagnostic criteria rather than to new environmental influences. Autism is not a disease but a syndrome with multiple nongenetic and genetic causes. By autism (the autistic spectrum disorders [ASDs]), we mean the wide spectrum of developmental disorders characterized by impairments in 3 behavioral domains: 1) social interaction; 2) language, communication, and imaginative play; and 3) range of interests and activities. Epidemiologic studies indicate that environmental factors such as toxic exposures, teratogens, perinatal insults, and prenatal infections such as rubella and cytomegalovirus account for few cases. These studies fail to confirm that immunizations with the measles-mumps-rubella vaccine are responsible for the surge in autism. Epilepsy, the medical condition most highly associated with autism, has equally complex genetic/nongenetic (but mostly unknown) causes. Autism is frequent in tuberous sclerosis complex and fragile X syndrome, but these 2 disorders account for but a small minority of cases. Currently, diagnosable medical conditions, cytogenetic abnormalities, and single-gene defects (eg, tuberous sclerosis complex, fragile X syndrome, and other rare diseases) together account for <10% of cases. There is convincing evidence that "idiopathic" autism is a heritable disorder. Epidemiologic studies report an ASD prevalence of ϳ3 to 6/1000, with a male to female ratio of 3:1. This skewed ratio remains unexplained: despite the contribution of a few well characterized X-linked disorders, male-to-male transmission in a number of families rules out X-linkage as the prevailing mode of inheritance. The recurrence rate in siblings of affected children is ϳ2% to 8%, much higher than the prevalence rate in the general population but much lower than in single-gene diseases. Twin studies reported 60% concordance for classic autism in monozygotic (MZ) twins versus 0 in dizygotic (DZ) twins, the higher MZ concordance attesting to genetic inheritance as the predominant causative agent. Reevaluation for a broader autistic phenotype that included communication and social disorders increased concordance remarkably from 60% to 92% in MZ twins and from 0% to 10% in DZ pairs. This suggests that interactions between multiple genes cause "idiopathic" autism but that epigenetic factors and exposure to environmental modifiers may contribute to variable expression of autism-related traits. The identity and number of genes involved remain unknown. The wide phenotypic variability of the ASDs likely reflects the interaction of multiple genes within an individual's genome and the existence of distinct genes and gene combinations among those affec...

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Section: E476mentioning

confidence: 91%

mentioning

confidence: 91%

The Genetics of Autism

2004

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“…The combined morphologic and FISH results allowed us to establish that 54% of the 241 sSMCs derived from acrocentric 12 ), accounting for a 10% frequency. The chromosomal origins of 33 rings from non-acrocentric chromosomes were also identified, that is, chromosomes X (n ϭ 4), 2 (n ϭ 4), 3 (n ϭ 4), 8 (n ϭ 4), 5 (n ϭ 3), 16 (n ϭ 3), 1 (n ϭ 2), 7 (n ϭ 2), 6 (n ϭ 1), 12 (n ϭ 1), 19 (n ϭ 1), and 1/5/19 (n ϭ 4).…”

Section: Chromosomal Originmentioning

confidence: 99%

Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: Cooperative study of 19 Italian laboratories

Dalprà

Giardino

Finelli

et al. 2005

Genetics in Medicine

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Purpose: We evaluated the experiences of 19 Italian laboratories concerning 241 small supernumerary marker chromosomes (sSMCs) with the aim of answering questions arising from their origin from any chromosome, their variable size and genetic content, and their impact on the carrier's phenotype. Methods: Conventional protocols were used to set up the cultures and chromosome preparations. Both commercial and homemade probes were used for the fluorescent in situ hybridization analyses. Results: A total of 113 of the 241 sSMCs were detected antenatally, and 128 were detected postnatally. There were 52 inherited and 172 de novo cases. Abnormal phenotype was present in 137 cases (57%), 38 of which were antenatally diagnosed. A mosaic condition was observed in 87 cases (36%). In terms of morphology, monocentric and dicentric bisatellited marker chromosomes were the most common, followed by monocentric rings and short-arm isochromosomes. The chromosomes generating the sSMCs were acrocentric in 132 cases (69%) and non-acrocentric chromosomes in 60 cases (31%); a neocentromere was hypothesized in three cases involving chromosomes 6, 8, and 15. The widespread use of molecular cytogenetic techniques in diagnostic laboratories has improved diagnostic quality, especially in prenatal cases. However, one of the few major problems remaining is the identification of the nature and origin of small supernumerary marker chromosomes (sSMCs).sSMCs display a wide range of morphology and occur at highly variable incidence, 1,2 thus giving rise to considerable problems in genetic counseling, particularly during prenatal testing. Only the combined use of conventional and molecular

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“…Regarding additional behavioural problems, a severe hyperactivity is often noticed. [19][20][21][22][23][24][25][26] Deletions of the maternal or paternal chromosome 15q11-13 regions are associated with two cytogenetic imprinting disorders, Angelman syndrome and Prader-Willi syndrome (PWS). Genomic imprinting describes the phenomenon of differences in gene expression between the allele inherited from the mother and the allele inherited from the father.…”

Section: Cytogenetic Findings and Genetic Syndromes In Admentioning

confidence: 99%

The genetics of autistic disorders and its clinical relevance: a review of the literature

2006

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Twin and family studies in autistic disorders (AD) have elucidated a high heritability of the narrow and broad phenotype of AD. In this review on the genetics of AD, we will initially delineate the phenotype of AD and discuss aspects of differential diagnosis, which are particularly relevant with regard to the genetics of autism. Cytogenetic and molecular genetic studies will be presented in detail, and the possibly involved aetiopathological pathways will be described. Implications of the different genetic findings for genetic counselling will be mentioned.

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Relationship between clinical and genetic features in “inverted duplicated chromosome 15” patients

Cited by 71 publications

References 24 publications

The Genetics of Autism

The Genetics of Autism

Cytogenetic and molecular evaluation of 241 small supernumerary marker chromosomes: Cooperative study of 19 Italian laboratories

The genetics of autistic disorders and its clinical relevance: a review of the literature

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