Dataset Information

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

ABSTRACT: Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental isodisomy (iUPD) on 5q32-qter in a patient with COS is described, which adds to the previously known high rates of chromosomal abnormalities reported in this sample. iUPD is a rare genetic condition in which the offspring receives two chromosomal homologues from one parent. Segmental UPD is defined as UPD on a portion of a chromosome with biparental inheritance seen in the rest of the homologous pair. Complications owing to this abnormality may arise from malfunctioning imprinted genes or homozygosity of recessive disease-causing mutations. This aberration became apparent during whole-genomic screening of a COS cohort and is of particular interest because 5q has been implicated in schizophrenia by several genomewide linkage studies and positive gene associations. This report, therefore, presents more evidence that schizophrenia susceptibility gene, or genes, may be found on distal 5q.

SUBMITTER: Seal JL

PROVIDER: S-EPMC2563188 | biostudies-literature | 2006 Nov

REPOSITORIES: biostudies-literature

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Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Seal J L JL Gornick M C MC Gogtay N N Shaw P P Greenstein D K DK Coffey M M Gochman P A PA Stromberg T T Chen Z Z Merriman B B Nelson S F SF Brooks J J Arepalli S S Wavrant-De Vrièze F F Hardy J J Rapoport J L JL Addington A M AM

Journal of medical genetics 20060608 11

Schizophrenia is a severe mental disorder affecting approximately 1% of the world's population. Although the aetiology of schizophrenia is complex and multifactorial, with estimated heritabilities as high as 80%, genetic factors are the most compelling. Childhood-onset schizophrenia (COS), defined as onset of schizophrenia before the age of 13 years, is a rare and malignant form of the illness that may have more salient genetic influence. The first known case of paternal segmental uniparental is ...[more]

PMID: 16763011

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Project description:LRBA deficiency was first described in 2012 as an autosomal recessive disorder caused by biallelic mutations in the LRBA gene (OMIM #614700). It was initially characterized as producing early-onset hypogammaglobulinemia, autoimmune manifestations, susceptibility to inflammatory bowel disease, and recurrent infection. However, further reports expanded this phenotype (including patients without hypogammaglobulinemia) and described LRBA deficiency as a clinically variable syndrome with a wide spectrum of clinical manifestations. We present the case of a female patient who presented with type 1 diabetes, psoriasis, oral thrush, and enlarged liver and spleen at the age of 8 months. She later experienced recurrent bacterial and viral infections, including pneumococcal meningitis and Epstein Barr viremia. She underwent two consecutive stem cell transplants at the age of 8 and 9 years, and ultimately died. Samples from the patient and her parents were subjected to whole exome sequencing, which revealed a homozygous 1-bp insertion in exon 23 of the patient's LRBA gene, resulting in frameshift and premature stop codon. The patient's healthy mother was heterozygous for the mutation and her father tested wild-type. This finding suggested that either one copy of the paternal chromosome 4 bore a deletion including the LRBA locus, or the patient inherited two copies of the mutant maternal LRBA allele. The patient's sequencing data showed a 1-Mb loss of heterozygosity region in chromosome 4, including the LRBA gene. Comparative genomic hybridization array of the patient's and father's genomic DNA yielded normal findings, ruling out genomic copy number abnormalities. Here, we present the first case of LRBA deficiency due to a uniparental disomy (UPD). In contrast to classical Mendelian inheritance, UPD involves inheritance of 2 copies of a chromosomal region from only 1 parent. Specifically, our patient carried a small segmental isodisomy of maternal origin affecting 1 Mb of chromosome 4.

Project description:BackgroundComplex genomic rearrangements (CGRs) consisting of interstitial triplications in conjunction with uniparental isodisomy (isoUPD) have rarely been reported in patients with multiple congenital anomalies (MCA)/intellectual disability (ID). One-ended DNA break repair coupled with microhomology-mediated break-induced replication (MMBIR) has been recently proposed as a possible mechanism giving rise to interstitial copy number gains and distal isoUPD, although only a few cases providing supportive evidence in human congenital diseases with MCA have been documented.Case presentationHere, we report on the chromosomal microarray (CMA)-based identification of the first known case with concurrent interstitial duplication at 1q42.12-q42.2 and triplication at 1q42.2-q43 followed by isoUPD for the remainder of chromosome 1q (at 1q43-qter). In distal 1q duplication/triplication overlapping with 1q42.12-q43, variable clinical features have been reported, and our 25-year-old patient with MCA/ID presented with some of these frequently described features. Further analyses including the precise mapping of breakpoint junctions within the CGR in a sequence level suggested that the CGR found in association with isoUPD in our case is a triplication with flanking duplications, characterized as a triplication with a particularly long duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure. Because microhomology was observed in both junctions between the triplicated region and the flanking duplicated regions, our case provides supportive evidence for recently proposed replication-based mechanisms, such as MMBIR, underlying the formation of CGRs?+?isoUPD implicated in chromosomal disorders.ConclusionsTo the best of our knowledge, this is the first case of CGRs?+?isoUPD observed in 1q and having DUP-TRP/INV-DUP structure with a long proximal duplication, which supports MMBIR-based model for genomic rearrangements. Molecular cytogenetic analyses using CMA containing single-nucleotide polymorphism probes with further analyses of the breakpoint junctions are recommended in cases suspected of having complex chromosomal abnormalities based on discrepancies between clinical and conventional cytogenetic findings.

Dataset Information

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

Publications

Segmental uniparental isodisomy on 5q32-qter in a patient with childhood-onset schizophrenia.

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