Details

Autor(en) / Beteiligte

• Costain, Gregory
• Lionel, Anath C
• Merico, Daniele
• Forsythe, Pamela
• Russell, Kathryn
• Lowther, Chelsea
• Yuen, Tracy
• Husted, Janice
• Stavropoulos, Dimitri J
• Speevak, Marsha
• Chow, Eva W C
• Marshall, Christian R
• Scherer, Stephen W
• Bassett, Anne S

Titel

Pathogenic rare copy number variants in community-based schizophrenia suggest a potential role for clinical microarrays

Ist Teil von

• Human molecular genetics, 2013-11, Vol.22 (22), p.4485-4501

Ort / Verlag

England: Oxford University Press

Erscheinungsjahr

2013

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Individually rare, large copy number variants (CNVs) contribute to genetic vulnerability for schizophrenia. Unresolved questions remain, however, regarding the anticipated yield of clinical microarray testing in schizophrenia. Using high-resolution genome-wide microarrays and rigorous methods, we investigated rare CNVs in a prospectively recruited community-based cohort of 459 unrelated adults with schizophrenia and estimated the minimum prevalence of clinically significant CNVs that would be detectable on a clinical microarray. A blinded review by two independent clinical cytogenetic laboratory directors of all large (>500 kb) rare CNVs in cases and well-matched controls showed that those deemed to be clinically significant were highly enriched in schizophrenia (16.4-fold increase, P < 0.0001). In a single community catchment area, the prevalence of individuals with these CNVs was 8.1%. Rare 1.7 Mb CNVs at 2q13 were found to be significantly associated with schizophrenia for the first time, compared with the prevalence in 23 838 population-based controls (42.9-fold increase, P = 0.0002). Additional novel findings that will facilitate the future clinical interpretation of smaller CNVs in schizophrenia include: (i) a greater proportion of individuals with two or more rare exonic CNVs >10 kb in size (1.5-fold increase, P = 0.0109) in schizophrenia; (ii) the systematic discovery of new candidate genes for schizophrenia; and, (iii) functional gene enrichment mapping highlighting a differential impact in schizophrenia of rare exonic deletions involving diverse functions, including neurodevelopmental and synaptic processes (4.7-fold increase, P = 0.0060). These findings suggest consideration of a potential role for clinical microarray testing in schizophrenia, as is now the suggested standard of care for related developmental disorders like autism.