Isochromosome 13 in a patient with childhood-onset schizophrenia, ADHD, and motor tic disorder

Abstract

BackgroundA small percentage of all cases of schizophrenia have a childhood onset. The impact on the individual and family can be devastating. We report the results of genetic analyses from a patient with onset of visual hallucinations at 5 years, and a subsequent diagnosis at 9 years of schizophrenia, attention deficit hyperactivity disorder (ADHD) with hyperactivity and impulsivity, and chronic motor tic disorder.ResultsKaryotypic analysis found 45,XX,i(13)(q10) in all cells examined. Alpha satellite FISH of isochromosome 13 revealed a large unsplit centromeric region, interpreted as two centromeres separated by minimal or undetectable short-arm material or as a single monocentric centromere, indicating that the isochromosome likely formed post-zygotically by a short arm U-type or centromeric exchange. Characterization of chromosome 13 simple tandem repeats and Affymetrix whole-genome 6.0 SNP array hybridization found homozygosity for all markers, and the presence of only a single paternal allele in informative markers, consistent with an isodisomic isochromosome of paternal origin. Analysis of two chromosome 13 schizophrenia candidate genes, D-amino acid oxidase activator (DAOA) and 5-hydroxytryptamine (serotonin) receptor 2A (5-HTR2A), failed to identify non-synonymous coding mutations but did identify homozygous risk polymorphisms.ConclusionsWe report a female patient with childhood-onset schizophrenia, ADHD, and motor tic disorder associated with an isodisomic isochromosome 13 of paternal origin and a 45,XX,i(13)(q10q10) karyotype. We examined two potential mechanisms to explain chromosome 13 involvement in the patient's pathology, including reduction to homozygosity of a paternal mutation and reduction to homozygosity of a paternal copy number variation, but were unable to identify any overtly pathogenic abnormality. Future studies may consider whether epigenetic mechanisms resulting from uniparental disomy (UPD) and the lack of chromosome 13 maternal alleles lead to the patient's features.

Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia

“…The karyotypes of all iPSC lines were assessed during glial differentiation to ensure genotypic stability of the cells utilized in all experiments presented here (karyotyping by WiCell, Madison, WI). All iPSCs showed a normal karyotype, except for line 51, which was found to have a balanced Robertsonian translocation of chromosome 13, an anomaly previously associated with juvenile-onset schizophrenia (Graw et al, 2012). …”

Structural and Functional Features of Developing Brain Capillaries, and Their Alteration in Schizophrenia

“…SCZ is recognized to be linked to genetic vulnerabilities ( Strawbridge et al, 2018 ; Chen et al, 2019 ; D’Ambrosio et al, 2019 ) (also reviewed in Comer et al, 2020a ) and environmental factors during adolescence and into young adulthood ( Pulver, 2000 ; Gomes and Grace, 2017 ; Qiu et al, 2019 ; Barichello et al, 2020 ). On the vascular level, genetic mutation on the chromosome 22q11 results in the loss of about 40 genes, one gene of interest being claudin-5 ( Graw et al, 2012 ; Tang et al, 2014 ; Thompson et al, 2017 ). In mice engineered with a mutation in 22q11, claudin-5 expression is reduced by 75% in ECs, which was reproduced in cell culture ( Greene et al, 2018 ).…”

Partial uniparental disomy with mosaic deletion 13q in an infant with multiple congenital anomalies

“…An interesting feature in our patient is that although only approximately 10% of cells have a deletion 13q in a peripheral blood sample, the patient shows many of the phenotypic features that are observed in distal 13 deletion cases. Maternal and paternal UPD13 have been previously reported [Slater et al, ; Stallard et al, ; Jarvela et al, ; Berend et al, ; Soler et al, ; Graw et al, ] and are associated with a normal phenotype. Therefore, the segmental maternal UPD may not have any phenotypic effects other than the possibility of unmasking a recessive mutation.…”