15q11.2 proximal imbalances associated with a diverse array of neuropsychiatric disorders and mild dysmorphic features.

*Section of Neurology, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO †Section of Developmental and Behavioral Science, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO ‡Department of Pathology, Children's Mercy Hospitals and Clinics and University of Missouri-Kansas City School of Medicine, Kansas City, MO.
Journal of developmental and behavioral pediatrics: JDBP (Impact Factor: 2.12). 08/2012; 33(7):570-6. DOI: 10.1097/DBP.0b013e31826052ae
Source: PubMed

ABSTRACT Deletion within the proximal region of chromosome 15q11.2 between breakpoints 1 and 2 (BP1-BP2) has been proposed to be a risk factor for intellectual disability, seizure, and schizophrenia. However, the clinical significance of its reciprocal duplication is not clearly defined yet. We evaluated 1654 consecutive pediatric patients with various neurological disorders by high-resolution microarray-based comparative genomic hybridization. We identified 21 patients carrying 15q11.2 BP1-BP2 deletion and 12 patients carrying 15q11.2 BP1-BP2 duplication in this cohort, which represent 1.27% (21/1,654) and 0.7% (12/1,654) of the patients analyzed, respectively. Approximately 87.5% of the patients carrying the deletion and 80% of the patients carrying the duplication have developmental delay or intellectual disability. Other recurrent clinical features in these patients include mild dysmorphic features, autistic spectrum disorders, and epilepsy. Our observations provide further evidence in favor of a strong association of 15q11.2 BP1-BP2 deletion with a variety of neuropsychiatric disorders. The diversity of clinical findings in these patients expands the phe-notypic spectrum of individuals carrying the deletion. In addition, possible etiological effects of 15q11.2 BP1-BP2 duplication in neuropsychiatric disorders are proposed.

Download full-text


Available from: Jean-Baptiste Le Pichon, Jul 05, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Proximal region of chromosome 15 long arm is rich in duplicons that, define five breakpoints (BP) for 15q rearrangements. 15q11.2 microdeletion between BP1 and BP2 has been previously associated with developmental delay and atypical psychological patterns. This region contains four highly-conserved and non-imprinted genes: NIPA1, NIPA2, CYFIP1, TUBGCP5. Our goal was to investigate the phenotypes associated with this microdeletion in a cohort of 52 patients. This copy number variation (CNV) was prevalent in 0.8% patients presenting with developmental delay, psychological pattern issues and/or multiple congenital malformations. This was studied by array-CGH at six different French Genetic laboratories. We collected data from 52 unrelated patients (including 3 foetuses) after excluding patients with an associated genetic alteration (known CNV, aneuploidy or known monogenic disease). Out of 52 patients, mild or moderate developmental delay was observed in 68.3%, 85.4% had speech impairment and 63.4% had psychological issues such as Attention Deficit and Hyperactivity Disorder, Autistic Spectrum Disorder or Obsessive-Compulsive Disorder. Seizures were noted in 18.7% patients and associated congenital heart disease in 17.3%. Parents were analysed for abnormalities in the region in 65.4% families. Amongst these families, `de novo` microdeletions were observed in 18.8% and 81.2% were inherited from one of the parents. Incomplete penetrance and variable expressivity were observed amongst the patients. Our results support the hypothesis that 15q11.2 (BP1-BP2) microdeletion is associated with developmental delay, abnormal behaviour, generalized epilepsy and congenital heart disease. The later feature has been rarely described. Incomplete penetrance and variability of expression demands further assessment and studies. Copyright © 2015. Published by Elsevier Masson SAS.
    European Journal of Medical Genetics 01/2015; 58(3). DOI:10.1016/j.ejmg.2015.01.002 · 1.49 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Developmental disorders, including intellectual disability, autism and attention deficit hyperactivity disorder (ADHD), are neuropsychiatric disorders that manifest in early childhood as deviations from the normal development. At present, in the majority of cases a cause cannot be found. However, in the past 5 years major advances have been made in the identification of specific genetic causes of these disorders. Here, we review these findings and discuss possible implications for our current understanding of the cause of developmental disorders. In addition to the disorders with known genetic cause that are associated with intellectual disability, autism and ADHD, an increasing number of novel recurrent structural variants are identified in association with these developmental disorders. These variants, as well as the genetic variants identified through sequencing approaches indicate the involvement of a large number of genes. Similar to what is the case for intellectual disability, recent genetic studies indicate a large degree of genetic heterogeneity for autism and ADHD. Many of the disease risk variants display incomplete penetrance, indicating that additional genetic, and possibly nongenetic, factors are relevant. Despite the high number of causative or contributing genes, functional studies of these genes indicate a large degree of convergence into a smaller number of neurobiological pathways. Elucidating these shared biological mechanisms is a crucial step towards the rational development of novel therapeutic interventions.
    Current opinion in neurology 04/2013; 26(2):128-36. DOI:10.1097/WCO.0b013e32835f1a30 · 5.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The recent explosion in the implementation of genome-wide microarray technology to discover rare, pathogenic genomic rearrangements in a variety of diseases has led to the discovery of numerous microdeletion syndromes. It is now clear that these microdeletions are associated with extensive phenotypic heterogeneity and incomplete penetrance. A subset of recurrent microdeletions underpin diverse phenotypes, including intellectual disability, autism, epilepsy and neuropsychiatric disorders. Recent studies highlight a role for additional low frequency variants, or 'second hits' to account for this variability. The implementation of massively parallel sequencing and epigenetic models may provide a powerful prospective approach to the delineation of microdeletion syndrome phenotypes.
    Current opinion in genetics & development 05/2013; 23(3). DOI:10.1016/j.gde.2013.03.004 · 8.57 Impact Factor