%0 Journal Article %J Hum Mutat %D 2018 %T Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. %A Grochowski, Christopher M %A Gu, Shen %A Yuan, Bo %A Tcw, Julia %A Brennand, Kristen J %A Sebat, Jonathan %A Malhotra, Dheeraj %A McCarthy, Shane %A Rudolph, Uwe %A Lindstrand, Anna %A Chong, Zechen %A Levy, Deborah L %A Lupski, James R %A Carvalho, Claudia M B %K Bipolar Disorder %K Chromosome Aberrations %K Chromosome Disorders %K Chromosome Duplication %K Chromosomes, Human, Pair 9 %K Comparative Genomic Hybridization %K Female %K Genetic Markers %K Humans %K In Situ Hybridization, Fluorescence %K Karyotyping %K Male %K Pedigree %K Phenotype %K Psychotic Disorders %K Whole Genome Sequencing %X

Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here, we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed three duplications and three triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline-level event in the proband's maternal grandmother. Whole-genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life-cycle genesis, and propose a DNA replicative/repair mechanism underlying formation.

%B Hum Mutat %V 39 %P 939-946 %8 2018 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/29696747?dopt=Abstract %R 10.1002/humu.23537 %0 Journal Article %J Stem Cell Reports %D 2017 %T Divergent Levels of Marker Chromosomes in an hiPSC-Based Model of Psychosis. %A Tcw, Julia %A Carvalho, Claudia M B %A Yuan, Bo %A Gu, Shen %A Altheimer, Alyssa N %A McCarthy, Shane %A Malhotra, Dheeraj %A Sebat, Jonathan %A Siegel, Arthur J %A Rudolph, Uwe %A Lupski, James R %A Levy, Deborah L %A Brennand, Kristen J %K Chromosome Duplication %K Chromosomes, Human %K Chromosomes, Human, Pair 9 %K Comparative Genomic Hybridization %K Genetic Association Studies %K Genetic Markers %K Genetic Predisposition to Disease %K Heterozygote %K Humans %K Induced Pluripotent Stem Cells %K Matrix Attachment Regions %K Mosaicism %K Psychotic Disorders %K Trisomy %X

In the process of generating presumably clonal human induced pluripotent stem cells (hiPSCs) from two carriers of a complex structural rearrangement, each having a psychotic disorder, we also serendipitously generated isogenic non-carrier control hiPSCs, finding that the rearrangement occurs as an extrachromosomal marker (mar) element. All confirmed carrier hiPSCs and differentiated neural progenitor cell lines were found to be mosaic. We caution that mar elements may be difficult to functionally evaluate in hiPSC cultures using currently available methods, as it is difficult to distinguish cells with and without mar elements in live mosaic cultures.

%B Stem Cell Reports %V 8 %P 519-528 %8 2017 Mar 14 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/28216146?dopt=Abstract %R 10.1016/j.stemcr.2017.01.010 %0 Journal Article %J NPJ Schizophr %D 2015 %T Characterization of molecular and cellular phenotypes associated with a heterozygous deletion using patient-derived hiPSC neural cells. %A Lee, Inkyu S %A Carvalho, Claudia M B %A Douvaras, Panagiotis %A Ho, Seok-Man %A Hartley, Brigham J %A Zuccherato, Luciana W %A Ladran, Ian G %A Siegel, Arthur J %A McCarthy, Shane %A Malhotra, Dheeraj %A Sebat, Jonathan %A Rapoport, Judith %A Fossati, Valentina %A Lupski, James R %A Levy, Deborah L %A Brennand, Kristen J %X

Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (). Traditionally, in animal models or , the function of has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in (affecting exons 14-15) and discordant clinical outcomes, we have characterized expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function.

%B NPJ Schizophr %V 1 %P 15019- %8 2015 Jun 24 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/26985448?dopt=Abstract %R 10.1038/npjschz.2015.19