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Both Rare and De Novo Copy Number Variants Are Prevalent in Agenesis of the Corpus Callosum but Not in Cerebellar Hypoplasia or Polymicrogyria
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نویسنده
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sajan s.a. ,fernandez l. ,nieh s.e. ,rider e. ,bukshpun p. ,wakahiro m. ,christian s.l. ,rivière j.-b. ,sullivan c.t. ,sudi j. ,herriges m.j. ,paciorkowski a.r. ,barkovich a.j. ,glessner j.t. ,millen k.j. ,hakonarson h. ,dobyns w.b. ,sherr e.h.
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منبع
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plos genetics - 2013 - دوره : 9 - شماره : 10
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چکیده
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Agenesis of the corpus callosum (acc),cerebellar hypoplasia (cblh),and polymicrogyria (pmg) are severe congenital brain malformations with largely undiscovered causes. we conducted a large-scale chromosomal copy number variation (cnv) discovery effort in 255 acc,220 cblh,and 147 pmg patients,and 2,349 controls. compared to controls,significantly more acc,but unexpectedly not cblh or pmg patients,had rare genic cnvs over one megabase (p = 1.48×10-3; odds ratio [or] = 3.19; 95% confidence interval [ci] = 1.89-5.39). rare genic cnvs were those that impacted at least one gene in less than 1% of the combined population of patients and controls. compared to controls,significantly more acc but not cblh or pmg patients had rare cnvs impacting over 20 genes (p = 0.01; or = 2.95; 95% ci = 1.69-5.18). independent qpcr confirmation showed that 9.4% of acc patients had de novo cnvs. these,in comparison to inherited cnvs,preferentially overlapped de novo cnvs previously observed in patients with autism spectrum disorders (p = 3.06×10-4; or = 7.55; 95% ci = 2.40-23.72). interestingly,numerous reports have shown a reduced corpus callosum area in autistic patients,and diminished social and executive function in many acc patients. we also confirmed and refined previously known cnvs,including significantly narrowing the 8p23.1-p11.1 duplication present in 2% of our current acc cohort. we found six novel cnvs,each in a single patient,that are likely deleterious: deletions of 1p31.3-p31.1,1q31.2-q31.3,5q23.1,and 15q11.2-q13.1; and duplications of 2q11.2-q13 and 11p14.3-p14.2. one acc patient with microcephaly had a paternally inherited deletion of 16p13.11 that included nde1. exome sequencing identified a recessive maternally inherited nonsense mutation in the non-deleted allele of nde1,revealing the complexity of acc genetics. this is the first systematic study of cnvs in congenital brain malformations,and shows a much higher prevalence of large gene-rich cnvs in acc than in cblh and pmg. © 2013 sajan et al.
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آدرس
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department of pediatrics,section of neurology,baylor college of medicine,houston,tx, United States, department of neurology,university of california,san francisco,san francisco,ca, United States, department of neurology,university of california,san francisco,san francisco,ca, United States, department of neurology,university of california,san francisco,san francisco,ca, United States, department of neurology,university of california,san francisco,san francisco,ca, United States, department of neurology,university of california,san francisco,san francisco,ca, United States, center for integrative brain research,seattle children's research institute,seattle,wa, United States, equipe génétique des anomalies du dévelopement,université de bourgogne,dijon, France, center for integrative brain research,seattle children's research institute,seattle,wa, United States, department of human genetics,university of chicago,chicago,il, United States, department of cell and developmental biology,university of pennsylvania,philadelphia,pa, United States, departments of neurology,pediatrics,and biomedical genetics,university of rochester medical center,rochester,ny, United States, department of radiology and biomedical imaging,division of neuroradiology,university of california,san francisco,san francisco,ca, United States, center for applied genomics,children's hospital of philadelphia,philadelphia,pa, United States, center for integrative brain research,seattle children's research institute,seattle,wa,united states,department of pediatrics,university of washington,seattle,wa, United States, center for applied genomics,children's hospital of philadelphia,philadelphia,pa,united states,department of pediatrics,the perelman school of medicine,university of pennsylvania,philadelphia,pa, United States, center for integrative brain research,seattle children's research institute,seattle,wa,united states,department of pediatrics,university of washington,seattle,wa,united states,department of neurology,university of washington,seattle,wa, United States, department of neurology,university of california,san francisco,san francisco,ca, United States
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Authors
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