Hogart A, Leung KN, Wang NJ, Wu DJ, Driscoll J, Vallero RO et al. Chromosome 15q11-13 duplication syndrome brain reveals epigenetic alterations in gene expression not predicted from copy number. J Med Genet 46: 86-93

Medical Microbiology and Immunology, School of Medicine, University of California-Davis, One Shields Avenue, Davis, CA 95616, USA.
Journal of Medical Genetics (Impact Factor: 6.34). 11/2008; 46(2):86-93. DOI: 10.1136/jmg.2008.061580
Source: PubMed


Chromosome 15q11-13 contains a cluster of imprinted genes essential for normal mammalian neurodevelopment. Deficiencies in paternal or maternal 15q11-13 alleles result in Prader-Willi or Angelman syndromes, respectively, and maternal duplications lead to a distinct condition that often includes autism. Overexpression of maternally expressed imprinted genes is predicted to cause 15q11-13-associated autism, but a link between gene dosage and expression has not been experimentally determined in brain.
Postmortem brain tissue was obtained from a male with 15q11-13 hexasomy and a female with 15q11-13 tetrasomy. Quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) was used to measure 10 15q11-13 transcripts in maternal 15q11-13 duplication, Prader-Willi syndrome, and control brain samples. Southern blot, bisulfite sequencing and fluorescence in situ hybridisation were used to investigate epigenetic mechanisms of gene regulation.
Gene expression and DNA methylation correlated with parental gene dosage in the male 15q11-13 duplication sample with severe cognitive impairment and seizures. Strikingly, the female with autism and milder Prader-Willi-like characteristics demonstrated unexpected deficiencies in the paternally expressed transcripts SNRPN, NDN, HBII85, and HBII52 and unchanged levels of maternally expressed UBE3A compared to controls. Paternal expression abnormalities in the female duplication sample were consistent with elevated DNA methylation of the 15q11-13 imprinting control region (ICR). Expression of non-imprinted 15q11-13 GABA receptor subunit genes was significantly reduced specifically in the female 15q11-13 duplication brain without detectable GABRB3 methylation differences.
Our findings suggest that genetic copy number changes combined with additional genetic or environmental influences on epigenetic mechanisms impact outcome and clinical heterogeneity of 15q11-13 duplication syndromes.

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    • "Hogart et al. provided some supporting evidence when they measured the level of 10 transcripts within the 15q11-13 region in two postmortem brains and found that the expression pattern correlated with parental gene dosage in the male patient. In the female brain, there was decreased expression of SNRPN, NDN, small nuclear RNAs (snoRNAs) and gamma-aminobutyric acide (GABA) A despite an increased dosage of genes of maternal origin [25]. In the case of SNRPN, the decreased expression was consistent with the finding of increased methylation found at the imprinting control region. "
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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.
    Full-text · Article · May 2014 · Molecular Cytogenetics
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    • "Partial trisomy 15q11-q13 is a well-known neurogenetic disorder that is characterized by clinical heterogeneity. A broad spectrum of moderate to severe symptoms including mental retardation, seizures, poor motor coordination, early-onset central hypotonia, autism spectrum disorders and mild dysmorphic features have been described [6-8]. Our patient had several features in common with previously described cases, including a low nasal bridge, micrognathia, short neck, clinodactyly of fifth fingers, hypotonia, failure to thrive and delayed neuropsychomotor development. "
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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.
    Full-text · Article · Apr 2014 · Molecular Cytogenetics
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    • "However, longitudinal studies are necessary to confirm the differences in neurodevelopmental trajectories between children with DEL and mUPD. An important genetic difference between individuals with DEL and mUPD is the overexpression of maternally imprinted UBE3A gene in brains of patients with mUPD [51]. UBE3A plays an important role in dendritic tree formation [52], and both knockout and overexpression of the UBE3A gene results in reduced growth and branching of the dendrites [52]. "
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    ABSTRACT: Prader--Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.
    Full-text · Article · Oct 2013 · Journal of Neurodevelopmental Disorders
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