The behavioral phenotype of the idic(15) syndrome

Postgraduate Medical School, University of Pisa, Italy.
American Journal of Medical Genetics Part C Seminars in Medical Genetics (Impact Factor: 3.91). 11/2010; 154C(4):448-55. DOI: 10.1002/ajmg.c.30281
Source: PubMed

ABSTRACT Idic(15) syndrome is a neurogenetic disorder clinically delineated by early central hypotonia, developmental delay and intellectual disability (ID), epilepsy, absent or very poor speech, and autistic or autistic-like behavior. It is due to the presence of a supernumerary marker chromosome formed by the inverted duplication of proximal chromosome 15, resulting in tetrasomy 15p and partial tetrasomy 15q, and containing the Prader-Willi/Angelman syndrome critical region (PWS/ASCR). The vast majority of these idic(15) derives from the two homologous maternal chromosomes at meiosis. To better define the behavior profile, we studied 22 idic(15) children (15 males and 7 females) observed at our institute between 1986 and 2010, and present, in detail, case studies of five of them. We have been able to perform standardized and semi-standardized measures of intelligence, and psychopathology in only 13 of our 22 patients, due to the limitations of chronological age, and to the severity of ID (ranging from mild-moderate, in 15%, to severe-profound, in 85% of our sample). The results show a distinct developmental profile in idic(15) patients, that may provide a behavioral signature for autism spectrum disorder (ASD)/ASD-like arising from the susceptibility locus on proximal 15q; and suggest that idic(15) individuals are not "true autistic," but distinct "autistic-like" persons with high score in the third ADOS-G and ADI-R area.

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    • "Cytogenetically visible duplications (OMIM #608636) and marker chromosomes from derivatives of this region are also common. The high frequency of such cases gave rise to a clinically recognizable disorder called 15q duplication syndrome, with some common neurobehavioural phenotypes [4]. Copy numbers of three, four, five and six have all been reported for this region [5-7]. "
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    ABSTRACT: Background The 15q11-q13 region contains many low copy repeats and is well known for its genomic instability. Several syndromes are associated with genomic imbalance or copy-number-neutral uniparental disomy. We report on two patients: Patient 1 is a boy with developmental delay and autism; and Patient 2 is a girl with developmental delay, hypotonia and dysmorphism. We performed analyses to delineate their dosage in the 15q region, determine whether the patients’ dosage correlates with phenotypic severity, and whether genes in the amplified regions are significantly associated with identified functional networks. Results For the proximal region of 15q, molecular cytogenetic analysis with Agilent oligonucleotide array showed a copy number of 3 for Patient 1 and a copy number of 4 for Patient 2. Fluorescent in situ hybridization analysis of Patient 2 showed two different populations of cells with different marker chromosomes. Methylation analysis of the amplified region showed that the extra copies of small nuclear ribonucleoprotein polypeptide N gene were of maternal origin. Phenotypic severity did not correlate with the size and dosage of 15q, or whether the amplification is interstitial or in the form of a supernumerary marker. Pathway analysis showed that in Patient 2, the main functional networks that are affected by the genes from the duplicated/triplicated regions are developmental disorder, neurological disease and hereditary disease. Conclusions The 15q11-q13 gains that were found in both patients could explain their phenotypic presentations. This report expands the cohort of patients for which 15q11-q13 duplications are molecularly characterized.
    Molecular Cytogenetics 05/2014; 7(1):32. DOI:10.1186/1755-8166-7-32 · 2.14 Impact Factor
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    • "Another frequent pattern was the slow, but global evolution of the adaptive behavior, social interaction, and communicative skills over time. The aforementioned findings suggest " a distinct developmental profile, that may provide a behavioral signature for ASD/ASD-like arising from the susceptibility locus on proximal 15q " [Battaglia et al., 2010, p. 454]. The same authors eventually proposed that " idic(15) individuals are not " true autistic " , but distinct " autistic-like persons " . "
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    ABSTRACT: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disabilities with various etiologies, but with a heritability estimate of more than 90%. Although the strong correlation between autism and genetic factors has been long established, the exact genetic background of ASD remains unclear. A number of genetic syndromes manifest ASD at higher than expected frequencies compared to the general population. These syndromes account for more than 10% of all ASD cases and include tuberous sclerosis, fragile X, Down, neurofibromatosis, Angelman, Prader-Willi, Williams, Duchenne, etc. Clinicians are increasingly required to recognize genetic disorders in individuals with ASD, in terms of providing proper care and prognosis to the patient, as well as genetic counseling to the family. Vice versa, it is equally essential to identify ASD in patients with genetic syndromes, in order to ensure correct management and appropriate educational placement. During investigation of genetic syndromes, a number of issues emerge: impact of intellectual disability in ASD diagnoses, identification of autistic subphenotypes and differences from idiopathic autism, validity of assessment tools designed for idiopathic autism, possible mechanisms for the association with ASD, etc. Findings from the study of genetic syndromes are incorporated into the ongoing research on autism etiology and pathogenesis; different syndromes converge upon common biological backgrounds (such as disrupted molecular pathways and brain circuitries), which probably account for their comorbidity with autism. This review paper critically examines the prevalence and characteristics of the main genetic syndromes, as well as the possible mechanisms for their association with ASD. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2013; 162(4). DOI:10.1002/ajmg.b.32152 · 3.42 Impact Factor
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    • "The idea that phenotypes are dependent on copy variants may not be correct and their underlying mechanisms are unlikely to be simple in humans. In contrast to the interstitial duplication of human chromosome 15q, termed idic (15) syndrome individuals, the presence of a supernumerary marker chromosome formed by the inverted duplication of proximal chromosome 15, resulting in partial tetrasomy 15q, often display increased, yet inappropriate, social behaviors (Battaglia et al. 2010). A gap between the mouse model and the human patient The mouse model for 15q duplication as an animal model for human neuropsychiatric disease fulfills construct validity, in which it possesses the same chromosomal abnormality as human patients. "
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    ABSTRACT: Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11-q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11-q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABA(A) subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11-q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11-q13 and their relationships to autism.
    Journal of Neurodevelopmental Disorders 07/2011; 3(3):270-81. DOI:10.1007/s11689-011-9088-1 · 3.27 Impact Factor
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