Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders

Lee, Jennifer A.; Lupski, James R.

doi:10.1016/j.neuron.2006.09.027

Cited by 250 publications

(214 citation statements)

References 239 publications

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“…Deletions will most likely create haploinsufficiency. There is no lack of examples of haploinsufficiency affecting neurological development, behavior, and cognition (30). The association of chromosomal abnormalities and submicroscopic deletions with autism supports the idea that gene imbalance can contribute to the disorder.…”

Section: Discussionmentioning

confidence: 76%

A unified genetic theory for sporadic and inherited autism

Zhao

Leotta

Kustanovich³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

292

280

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Autism is among the most clearly genetically determined of all cognitive-developmental disorders, with males affected more often than females. We have analyzed autism risk in multiplex families from the Autism Genetic Resource Exchange (AGRE) and find strong evidence for dominant transmission to male offspring. By incorporating generally accepted rates of autism and sibling recurrence, we find good fit for a simple genetic model in which most families fall into two types: a small minority for whom the risk of autism in male offspring is near 50%, and the vast majority for whom male offspring have a low risk. We propose an explanation that links these two types of families: sporadic autism in the low-risk families is mainly caused by spontaneous mutation with high penetrance in males and relatively poor penetrance in females; and high-risk families are from those offspring, most often females, who carry a new causative mutation but are unaffected and in turn transmit the mutation in dominant fashion to their offspring.human genetics ͉ neurodevelopmental disorders ͉ population genetics A utism Spectrum Disorder (ASD) (Online Mendelian Inheritance in Man accession no. 209850) is characterized by language impairments, social deficits, and repetitive behaviors; can occur either sporadically (simplex) or in a familial (multiplex) pattern; occurs far more commonly in males; and has an overall incidence of Ϸ1 in 150 births (1). Monozygotic (MZ) twins show Ͼ70% concordance (2), higher with broader diagnostic criteria, and much higher than observed in dizygotic (DZ) twins, strongly suggesting that autism is genetically determined. Children with affected siblings have a higher risk than the general population, suggesting that autism can be inherited at least partially from preexisting genetic variants in parents.Autism is likely to involve many genes. Linkage studies find no single locus of major effect but rather a very minor increase in allele sharing over the entire genome among concordant sibs (3-9). Cytogenetic studies (10), and more recently copy number analyses (9,11,12), support the idea that many loci may contribute to the disease.Sibling and DZ concordance rates are perhaps one-tenth of MZ concordance rates, and this discrepancy, plus the suggestion of a large number of risk loci, has led many to expect that autism is attributable to complex multigenic interactions rather than simple dominant or recessive mutations. However, our current knowledge of genetic factors in autism suggests otherwise. Most of what we know about heritable risk factors comes from monogenic disorders, including fragile X syndrome (13-15), Rett syndrome (16), and tuberous sclerosis (17). Furthermore, cytogenetic findings and, more recently, copy number analysis point to a higher incidence of spontaneous mutation in children with sporadic autism (11), presumably occurring in a parental germ line.An alternate to the multigenic interaction hypothesis is worth considering; most cases of autism are due to de novo mutation in the parental germ li...

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Section: Discussionmentioning

confidence: 76%

A unified genetic theory for sporadic and inherited autism

Zhao

Leotta

Kustanovich³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

292

280

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“…Chromosomal abnormalities have been reported in patients with schizophrenia, bipolar disorder and major depression, 55,56 but it is not clear to what extent CNVs contribute to variation in behavior. It is noteworthy that CNVs on chromosome 17 (enriched for high log P values) contain two genes involved in behavior, that is, the Tau gene (MAPT) and the corticotropinreleasing hormone receptor-1 (CRHR1).…”

Section: Discussionmentioning

confidence: 99%

A whole genome association study of neuroticism using DNA pooling

et al. 2007

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We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from B2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had B80% power to identify neuroticism loci in the genome with odds ratio (OR) > 2, and B50% power to identify small effects (OR = 1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

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“…Such DNA segments of 1 kb or larger that are present as variable copy numbers (CNVs) are known to alter gene dosage, interfere with coding sequences and have generegulating effects. For example, three instead of two copies of the normal PMP22 gene causes serious neurological Functional genomics applied to dairy cow fertility disease (Lee and Lupski, 2006). For a population of humans, Redon et al (2006) found that 12% of the genome consisted of copy number variable regions, and since this encompasses more nucleotide content than SNPs, the contribution of CNVs to phenotypic variation may be substantial.…”

Section: Rna Interferencementioning

confidence: 99%

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Beerda

Wyszyńska-Koko

Pas

et al. 2008

Animal

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Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility.

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Genomic Rearrangements and Gene Copy-Number Alterations as a Cause of Nervous System Disorders

Cited by 250 publications

References 239 publications

A unified genetic theory for sporadic and inherited autism

A unified genetic theory for sporadic and inherited autism

A whole genome association study of neuroticism using DNA pooling

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

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