Homozygosity mapping in outbred families with mental retardation

Schuurs-Hoeijmakers, Janneke; Hehir-Kwa, Jayne Y.; Pfundt, Rolph; Bon, Bregje W.M. van; Leeuw, Nicole de; Kleefstra, Tjitske; Willemsen, M.A.A.P.; Kessel, Ad Geurts van; Brunner, Han G.; Veltman, Joris A.; Bokhoven, Hans van; Brouwer, Arjan P.M. de; Vries, Bert B.A. de

doi:10.1038/ejhg.2010.167

Cited by 25 publications

(20 citation statements)

References 20 publications

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“…To date, research on the relationship between inbreeding and cognitive ability has largely been restricted to recent inbreeding events as determined by pedigree, although one genome-wide study of ancestral inbreeding has been reported for 10 unrelated families each with two mentally retarded siblings. 4 It has been suggested that intellectual disability is under negative selection, and that recent deleterious mutations have an important role in the underlying aetiology. 5,6 The wealth of molecular genetic data currently available allows estimates of inbreeding on a genome-wide level and to examine the effects of long-term ancestral levels of inbreeding.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

et al. 2013

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The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin-cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P ¼ 0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P ¼ 0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

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Section: Introductionmentioning

confidence: 99%

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

et al. 2013

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“…We and others have shown that the autozygome approach can be very effective in guiding the mutation analysis (Aldahmesh et al 2009;Pomares et al 2010). Interestingly, this approach was also used successfully in populations where consanguinity is uncommon (Hildebrandt et al 2009;Collin et al 2011;Hagiwara et al 2011;Schuurs-Hoeijmakers et al 2011). However, this approach has its limitations.…”

Section: Autozygome/exome Analysis In Retinal Dystrophymentioning

confidence: 99%

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

et al. 2012

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Retinal dystrophy (RD) is a heterogeneous group of hereditary diseases caused by loss of photoreceptor function and contributes significantly to the etiology of blindness globally but especially in the industrialized world. The extreme locus and allelic heterogeneity of these disorders poses a major diagnostic challenge and often impedes the ability to provide a molecular diagnosis that can inform counseling and gene-specific treatment strategies. In a large cohort of nearly 150 RD families, we used genomic approaches in the form of autozygome-guided mutation analysis and exome sequencing to identify the likely causative genetic lesion in the majority of cases. Additionally, our study revealed six novel candidate disease genes (C21orf2, EMC1, KIAA1549, GPR125, ACBD5, and DTHD1), two of which (ACBD5 and DTHD1) were observed in the context of syndromic forms of RD that are described for the first time.

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“…Based on the estimated 10-12% fraction of X-linked genes that can lead to MR, a minimum estimate for the number of autosomal MR genes could be as high as 800-850, many of which are sensitive to dosage changes [Ropers, 2010]. Other estimates predict up to 2,000 autosomal genes involved in MR [Schuurs-Hoeijmakers et al, 2011].…”

Section: Idiopathic Mental Retardation With or Without Congenital Abnmentioning

confidence: 99%

Genome Arrays for the Detection of Copy Number Variations in Idiopathic Mental Retardation, Idiopathic Generalized Epilepsy and Neuropsychiatric Disorders: Lessons for Diagnostic Workflow and Research

Hochstenbach

Buizer-Voskamp²,

Vorstman

et al. 2011

Cytogenet Genome Res

104

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We review the contributions and limitations of genome-wide array-based identification of copy number variants (CNVs) in the clinical diagnostic evaluation of patients with mental retardation (MR) and other brain-related disorders. In unselected MR referrals a causative genomic gain or loss is detected in 14–18% of cases. Usually, such CNVs arise de novo, are not found in healthy subjects, and have a major impact on the phenotype by altering the dosage of multiple genes. This high diagnostic yield justifies array-based segmental aneuploidy screening as the initial genetic test in these patients. This also pertains to patients with autism (expected yield about 5–10% in nonsyndromic and 10–20% in syndromic patients) and schizophrenia (at least 5% yield). CNV studies in idiopathic generalized epilepsy, attention-deficit hyperactivity disorder, major depressive disorder and Tourette syndrome indicate that patients have, on average, a larger CNV burden as compared to controls. Collectively, the CNV studies suggest that a wide spectrum of disease-susceptibility variants exists, most of which are rare (<0.1%) and of variable and usually small effect. Notwithstanding, a rare CNV can have a major impact on the phenotype. Exome sequencing in MR and autism patients revealed de novo mutations in protein coding genes in 60 and 20% of cases, respectively. Therefore, it is likely that arrays will be supplanted by next-generation sequencing methods as the initial and perhaps ultimate diagnostic tool in patients with brain-related disorders, revealing both CNVs and mutations in a single test.

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Homozygosity mapping in outbred families with mental retardation

Cited by 25 publications

References 20 publications

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

Autozygome-guided exome sequencing in retinal dystrophy patients reveals pathogenetic mutations and novel candidate disease genes

Genome Arrays for the Detection of Copy Number Variations in Idiopathic Mental Retardation, Idiopathic Generalized Epilepsy and Neuropsychiatric Disorders: Lessons for Diagnostic Workflow and Research

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