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Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother

AP-HP, Robert Debré Hospital, Department of Genetics, Cytogenetics Unit, Paris, France .
European journal of human genetics: EJHG (Impact Factor: 4.23). 01/2012; 20(5):540-6. DOI: 10.1038/ejhg.2011.244
Source: PubMed

ABSTRACT The pericentromeric region of chromosome 16p is rich in segmental duplications that predispose to rearrangements through non-allelic homologous recombination. Several recurrent copy number variations have been described recently in chromosome 16p. 16p11.2 rearrangements (29.5-30.1 Mb) are associated with autism, intellectual disability (ID) and other neurodevelopmental disorders. Another recognizable but less common microdeletion syndrome in 16p11.2p12.2 (21.4 to 28.5-30.1 Mb) has been described in six individuals with ID, whereas apparently reciprocal duplications, studied by standard cytogenetic and fluorescence in situ hybridization techniques, have been reported in three patients with autism spectrum disorders. Here, we report a multiplex family with three boys affected with autism, including two monozygotic twins carrying a de novo 16p11.2p12.2 duplication of 8.95 Mb (21.28-30.23 Mb) characterized by single-nucleotide polymorphism array, encompassing both the 16p11.2 and 16p11.2p12.2 regions. The twins exhibited autism, severe ID, and dysmorphic features, including a triangular face, deep-set eyes, large and prominent nasal bridge, and tall, slender build. The eldest brother presented with autism, mild ID, early-onset obesity and normal craniofacial features, and carried a smaller, overlapping 16p11.2 microdeletion of 847 kb (28.40-29.25 Mb), inherited from his apparently healthy father. Recurrent deletions in this region encompassing the SH2B1 gene were recently reported in early-onset obesity and in individuals with neurodevelopmental disorders associated with phenotypic variability. We discuss the clinical and genetic implications of two different 16p chromosomal rearrangements in this family, and suggest that the 16p11.2 deletion in the father predisposed to the formation of the duplication in his twin children.

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    • "appear in up to 1% of individuals with autism [61] [62], making copy number variations of the 16p11.2 region one of the most common genetic abnormalities implicated in autism [63] [64]. "
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    ABSTRACT: Mouse models offer indispensable heuristic tools for studying genetic and environmental causes of neuropsychiatric disorders, including autism. Development of useful animal models of complex human behaviors depends not only on extensive knowledge of the human disease, but also on a deep understanding of animal behavior and ethology. Robert and Caroline Blanchard pioneered a number of elegant social paradigms in rodents. Their early work led to systematic delineations of rodent naturalist defensive behaviors, which were proven to be highly useful models of human psychiatric disorders, including fear and anxiety. Their work using the Visible Burrow System to study social stress in rats represented an unprecedented approach to study biological mechanisms of depression. In recent years, their extensive knowledge of mouse behavior and ethology enabled them to quickly become leading figures in the field of behavioral genetics of autism. To commemorate Robert Blanchard's influences on animal models of human psychiatric disorders, here we describe a study conceptualized and led by Mu Yang who was trained as a graduate student in the Blanchard laboratory in the early 2000s. This investigation focuses on social housing in a genetic mouse model of 16p11.2 deletion syndrome. Heterozygous deletions and duplications of a segment containing about 29 genes on human chromosome 16 appear in approximately 0.5-1% of all cases of autism. 16p11.2 deletion syndrome is also associated with intellectual disabilities and speech impairments. Our previous studies showed that a mouse model of 16p11.2 deletion syndrome exhibited deficits in vocalizations and novel object recognition, as compared to wildtype littermate control cagemates. In the spirit of Bob Blanchard's careful attention to the role of social dominance in rodent behaviors, we became interested in the question of whether behavioral outcomes of a mutation differ when mutants are housed in mixed genotype cages, versus housing only mutants together in one group cage, and only wildtype littermates together in another group cage after weaning. 16p11.2 deletion presented a particularly good model organism to investigate this question, because the heterozygotes are smaller than their wildtype littermates, and may therefore become subordinate to their larger cagemates. Wild type and heterozygotes were housed with cagemates of the same genotype (same-genotype cage) or with cagemates of the opposite genotype (mixed-genotype cage). Current results replicated social vocalization and object recognition deficits that we previously found in heterozygotes lived in mixed-genotype cages. In contrast, heterozygotes that lived in same-genotype cages emitted normal numbers of vocalizations during male-female interactions, and displayed normal novel object recognition, indicating that the deletion per se was not sufficient to cause cognitive or social deficits. Social approach, same-sex social interaction, anxiety-related behavior, depression-related behavior, and open field exploration were not different between genotypes, and were not affected by housing in mixed versus in same-genotype cages. These findings suggest that elements of the home cage social environment could interact with genotype to impact aspects of disease phenotypes. Current findings are discussed as potentially reflecting behavioral deficits resulted from social stress, as inspired by a seminal paper by Bob and Caroline Blanchard [1]. Copyright © 2015. Published by Elsevier Inc.
    Physiology & Behavior 04/2015; 146. DOI:10.1016/j.physbeh.2015.04.023 · 3.03 Impact Factor
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    • "Tabet et al. [11] discussed the clinical and genetic implications of two different 16p chromosomal rearrangements in a family with three boys affected by autism. Two of the boys were monozygotic twins, displaying – in addition to autism - severe intellectual deficiency, triangular facial structure, deep-set eyes, large and prominent nasal bridge, and a tall-slender build. "
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    ABSTRACT: Background Complex small supernumerary marker chromosomes (sSMCs) consist of chromosomal material derived from more than one chromosome and have been implicated in reproductive problems such as recurrent pregnancy loss. They may also be associated with congenital abnormalities in the offspring of carriers. Due to its genomic architecture, chromosome 15 is frequently associated with rearrangements and the formation of sSMCs. Recently, several different CNVs have been described at 16p11.2, suggesting that this region is prone to rearrangements. Results We detected the concomitant occurrence of partial trisomy 15q and 16p, due to a complex sSMC, in a 6-year-old girl with clinical phenotypic. The karyotype was analyzed by G and C banding, NOR staining, FISH and SNP array and defined as 47,XX,+der(15)t(15;16)(q13;p13.2)mat. The array assay revealed an unexpected complex sSMC containing material from chromosomes 15 and 16, due to an inherited maternal translocation (passed along over several generations). The patient’s phenotype included microsomia, intellectual disability, speech delay, hearing impairment, dysphagia and other minor alterations. Discussion This is the first report on the concomitant occurrence of partial trisomy 15q and 16p. The wide range of phenotypes associated with complex sSMCs represents a challenge for genotype-phenotype correlation studies, accurate clinical assessment of patients and genetic counseling.
    Molecular Cytogenetics 04/2014; 7:29. DOI:10.1186/1755-8166-7-29 · 2.66 Impact Factor
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    • "Reciprocal duplications of 16p12.2–p11.2 have been reported in some patients with mild to severe intellectual disability, ASD, and dysmorphic features [Engelen et al., 2002; Finelli et al., 2004; Ballif et al., 2007; Tabet et al., 2012; Barber et al., 2013]. The 16p12.2–p11.2 "
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    ABSTRACT: The short arm of chromosome 16 is rich in segmental duplications that result in chromosomal rearrangements through non-allelic homologous recombination. Several syndromes resulting from microdeletions or microduplications in this region have been reported. The chromosome 16p12.2-p11.2 deletion syndrome, 7.1- to 8.7-Mb [OMIM#613604] is characterized by minor facial anomalies, feeding difficulties, a significant delay in speech development, and recurrent ear infections. Reciprocal duplications of 16p12.2-p11.2 have been reported in some patients with autism. We identified a patient with a 16p12.2-p11.2 deletion and a patient with a 16p12.2-p11.2 duplication using oligonucleotide SNP array. The patient with the deletion showed severe developmental delay without autism. The patient with the deletion shared clinical features with previously reported patients. The patient with the duplication showed mild developmental delay and autism. She had dysmorphic features including a round face, a large mouth, and relative macrocephaly. We reviewed the reports of the two syndromes and compared the clinical manifestations. The 16p12.2-p11.2 duplication syndrome is a new syndrome with autism spectral disorders and dysmorphic features. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 01/2014; 164(1). DOI:10.1002/ajmg.a.36217 · 2.05 Impact Factor
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