Publications by authors named "Moyra Smith"

17 Publications

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MRNA Transcription, Translation, and Defects in Developmental Cognitive and Behavioral Disorders.

Authors:
Moyra Smith

Front Mol Biosci 2020 25;7:577710. Epub 2020 Sep 25.

Department of Pediatrics, University of California, Irvine, Irvine, CA, United States.

The growth of expertise in molecular techniques, their application to clinical evaluations, and the establishment of databases with molecular genetic information has led to greater insights into the roles of molecular processes related to gene expression in neurodevelopment and functioning. The goal of this review is to examine new insights into messenger RNA transcription, translation, and cellular protein synthesis and the relevance of genetically determined alterations in these processes in neurodevelopmental, cognitive, and behavioral disorders.
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http://dx.doi.org/10.3389/fmolb.2020.577710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7545264PMC
September 2020

mitochondrial disease: new patients and review of the genetic and clinical spectrum.

J Med Genet 2021 05 9;58(5):314-325. Epub 2020 Jun 9.

Population Bio, Inc, New York, New York, USA

Background: The nucleotide binding protein-like () gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families).

Methods: Whole exome sequencing was used to identify patients with compound heterozygous variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model () and mitochondrial respiration experiments on patient fibroblasts.

Results: The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found with c.815-27T>C, but only two of four families had both variants. The second variant found with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3-18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity.

Conclusion: We report on five new patients with disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic variants.
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http://dx.doi.org/10.1136/jmedgenet-2020-106846DOI Listing
May 2021

Ethnic disparities in the frequency of cancer reported in family histories.

J Genet Couns 2020 06 28;29(3):451-459. Epub 2020 Mar 28.

Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California, Irvine, Irvine, California.

This study was designed to observe whether disparities exist between ethnicities in reporting a family history of cancer in a cancer genetic counseling clinic. Four hundred sixty-nine pedigrees collected between 2015 to 2017 from a cancer clinic at the University of California, Irvine, were analyzed. Pedigrees were separated by ethnicity into the following categories: non-Hispanic White, Hispanic, Asian, or Ashkenazi Jewish. The number of first- and second-degree relatives was calculated for each pedigree, and the total number of relatives reported with cancer. The total reported with cancer was divided by total number of relatives to derive a percentage of cancer reporting for each pedigree. The percentages of cancer reporting were analyzed using column proportions, nonparametric tests, and a Poisson regression. Cancer reporting in first- and second-degree relatives was highest among non-Hispanic Whites and Ashkenazi Jewish individuals, with median percentages of 22% and 27%, respectively. The median percentage of cancer reporting in first- and second-degree relatives in both Hispanics and Asians was 10%. Cancer reporting medians were significantly lower in Hispanics and Asians when compared to non-Hispanic Whites and Ashkenazi Jewish individuals (p < .001). Ethnicity was a significant factor for predicting the number of relatives reported to have cancer when analyzed with a Poisson regression. This study concluded that cancer is reported less frequently in families when the proband and their families are Hispanic or Asian. Hispanics and Asians have lower cancer incidence rates; however, incidence rates alone may not explain the reporting disparity observed. Hence, family cancer histories in minority populations may be truncated. Healthcare professionals should be aware of this disparity when assessing cancer risks so appropriate modifications can be made accordingly for recommended cancer screening and/or cancer genetic testing. Further efforts are warranted to disseminate information to minority populations about the value of family health history regarding cancer risk assessment.
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http://dx.doi.org/10.1002/jgc4.1264DOI Listing
June 2020

Expanded Insights Into Mechanisms of Gene Expression and Disease Related Disruptions.

Front Mol Biosci 2018 27;5:101. Epub 2018 Nov 27.

Department of Pediatrics, University of California, Irvine, Irvine, CA, United States.

Definitive molecular diagnoses in disorders apparently due to genetic or genomic defects are still lacking in a significant number of investigated cases, despite use of studies designed to discover defects in the protein coding regions of the genome. Increasingly studies are being designed to search for defects in the non-protein coding genome, and for alterations in gene expression. Here we review new insights into genomic elements involved in control of gene expression, including methods to analyze chromatin that is accessible for transcription factor binding, enhancers, chromatin looping, transcription, RNA binding proteins, and alternative splicing. We review new studies on levels of genome organization, including the occurrence of transcriptional domains and their boundary elements. Information is presented on specific malformation syndromes that arise due to structural genomic changes that impact the non-protein coding genome and sometimes impact specific transcriptional domains. We also review convergence of genome-wide association with studies of gene expression, discoveries related to expression quantitative trait loci and splicing quantitative trait loci and the relevance of these to specific complex common diseases. Aspects of epigenetic mechanisms and clinical applications of analyses of methylation signatures are also discussed.
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http://dx.doi.org/10.3389/fmolb.2018.00101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277798PMC
November 2018

Meta-analysis of genotype-phenotype analysis of OPA1 mutations in autosomal dominant optic atrophy.

Mitochondrion 2019 05 27;46:262-269. Epub 2018 Aug 27.

Division of Genetics and Genomic Medicine, Department of Pediatrics, University of California, Irvine, CA, USA. Electronic address:

Autosomal Dominant Optic Atrophy (ADOA) is a neuro-ophthalmic disease characterized by progressive bilateral vision loss, pallor of the optic disc, central vision loss, and impairment of color vision. Additionally, a small percentage of patients experience hearing loss and ataxia, while recent studies suggest disruption of cardiac and neuromuscular functions. In order to obtain a better understanding of the genotype-phenotype correlation of the various mutations in the optic atrophy 1 (OPA1) gene, we obtained both clinical and genetic information of ADOA patients from published reports. We conducted a systematic review of published OPA1 literature and identified 408 individuals with confirmed OPA1 mutations, 120 of whom reported extra-ocular (ADOA 'plus') manifestations through their descriptions of visual and multi-systemic symptoms. Our results show that there is a significant variation in frequency of the specific exons involved between the ADOA classic and ADOA 'plus' patients. Classic ADOA groups were more likely to have mutations in exon 8 and 9, while ADOA 'plus' groups were more likely to have mutations in exons 14, 15 and 17. Additional comparisons revealed significant differences between mutation types/domains and specific ADOA 'plus' manifestations. We also found that individuals with maternally inherited OPA1 mutations were significantly more likely to develop 'plus' manifestations than those with paternally inherited mutations. Overall, this study provides novel information regarding genotype-phenotype correlations of ADOA which warrants additional recommendations added to the current clinical management of ADOA patients.
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http://dx.doi.org/10.1016/j.mito.2018.07.006DOI Listing
May 2019

DNA Sequence Analysis in Clinical Medicine, Proceeding Cautiously.

Authors:
Moyra Smith

Front Mol Biosci 2017 3;4:24. Epub 2017 May 3.

Genetics and Genomic Medicine, Pediatrics, School of Medicine, University of CaliforniaIrvine, CA, USA.

Delineation of underlying genomic and genetic factors in a specific disease may be valuable in establishing a definitive diagnosis and may guide patient management and counseling. In addition, genetic information may be useful in identification of at risk family members. Gene mapping and initial genome sequencing data enabled the development of microarrays to analyze genomic variants. The goal of this review is to consider different generations of sequencing techniques and their application to exome sequencing and whole genome sequencing and their clinical applications. In recent decades, exome sequencing has primarily been used in patient studies. Discussed in some detail, are important measures that have been developed to standardize variant calling and to assess pathogenicity of variants. Examples of cases where exome sequencing has facilitated diagnosis and led to improved medical management are presented. Whole genome sequencing and its clinical relevance are presented particularly in the context of analysis of nucleotide and structural genomic variants in large population studies and in certain patient cohorts. Applications involving analysis of cell free DNA in maternal blood for prenatal diagnosis of specific autosomal trisomies are reviewed. Applications of DNA sequencing to diagnosis and therapeutics of cancer are presented. Also discussed are important recent diagnostic applications of DNA sequencing in cancer, including analysis of tumor derived cell free DNA and exosomes that are present in body fluids. Insights gained into underlying pathogenetic mechanisms of certain complex common diseases, including schizophrenia, macular degeneration, neurodegenerative disease are presented. The relevance of different types of variants, rare, uncommon, and common to disease pathogenesis, and the continuum of causality, are addressed. Pharmogenetic variants detected by DNA sequence analysis are gaining in importance and are particularly relevant to personalized and precision medicine.
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http://dx.doi.org/10.3389/fmolb.2017.00024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413496PMC
May 2017

Mitochondrial and ion channel gene alterations in autism.

Biochim Biophys Acta 2012 Oct 17;1817(10):1796-802. Epub 2012 Apr 17.

Department of Pediatrics University of California, Irvine, CA, USA.

To evaluate the potential importance in autistic subjects of copy number variants (CNVs) that alter genes of relevance to bioenergetics, ionic metabolism, and synaptic function, we conducted a detailed microarray analysis of 69 autism probands and 35 parents, compared to 89 CEU HapMap controls. This revealed that the frequency CNVs of≥100kb and CNVs of≥10 Kb were markedly increased in probands over parents and in probands and parents over controls. Evaluation of CNVs≥1Mb by chromosomal FISH confirmed the molecular identity of a subset of the CNVs, some of which were associated with chromosomal rearrangements. In a number of the cases, CNVs were found to alter the copy number of genes that are important in mitochondrial oxidative phosphorylation (OXPHOS), ion and especially calcium transport, and synaptic structure. Hence, autism might result from alterations in multiple bioenergetic and metabolic genes required for mental function. This article is part of a Special Issue entitled: 17th European Bioenergetics Conference (EBEC 2012).
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http://dx.doi.org/10.1016/j.bbabio.2012.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423964PMC
October 2012

Nuclear and mitochondrial genome defects in autisms.

Ann N Y Acad Sci 2009 Jan;1151:102-32

Department of Pediatrics, University of California-Irvine, Irvine, CA 92697, USA.

In this review we will evaluate evidence that altered gene dosage and structure impacts neurodevelopment and neural connectivity through deleterious effects on synaptic structure and function, and evidence that the latter are key contributors to the risk for autism. We will review information on alterations of structure of mitochondrial DNA and abnormal mitochondrial function in autism and indications that interactions of the nuclear and mitochondrial genomes may play a role in autism pathogenesis. In a final section we will present data derived using Affymetrix SNP 6.0 microarray analysis of DNA of a number of subjects and parents recruited to our autism spectrum disorders project. We include data on two sets of monozygotic twins. Collectively these data provide additional evidence of nuclear and mitochondrial genome imbalance in autism and evidence of specific candidate genes in autism. We present data on dosage changes in genes that map on the X chromosomes and the Y chromosome. Precise analyses of Y located genes are often difficult because of the high degree of homology of X- and Y-related genes. However, continued efforts to analyze the latter are important, given the consistent evidence for a 4:1 ratio of males to females affected by autism. It is also important to consider whether environmental factors play a role in generating the nuclear and mitochondrial genomic instability we have observed. The study of autism will benefit from a move to analysis of pathways and multigene clusters for identification of subtypes that share a specific genetic etiology.
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http://dx.doi.org/10.1111/j.1749-6632.2008.03571.xDOI Listing
January 2009

The year in human and medical genetics. Highlights of 2007-2008.

Authors:
Moyra Smith

Ann N Y Acad Sci 2009 Jan;1151:1-21

Pediatrics, College of Health Sciences, University of California-Irvine, Irvine, CA 92697, USA.

The breadth and scope of new information makes difficult a selection of topics to be included in a limited review of highlights of the year. Admittedly, the choices are idiosyncratic. The eight topics presented here are (1) structural and copy number variants in the human genome; (2) progress in defining genetic factors in the etiology of schizophrenia; (3) microRNAs in central nervous system development and function; (4) progress in elucidation of risk factors for complex common disorders through large scale association studies; (5) epigenetics and the epigenomic era; (6) reprogramming of somatic cell nuclei to generate pluripotent stem cells; (7) new concepts regarding factors involved in sexual differentiation; and (8) Duffy blood group antigens: new concepts, and new discoveries on the role of these antigens in malaria and HIV-AIDS.
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http://dx.doi.org/10.1111/j.1749-6632.2008.03608.xDOI Listing
January 2009

Preface. The year in human and medical genetics.

Authors:
Moyra Smith

Ann N Y Acad Sci 2009 Jan;1151:ix-x

Department of Pediatrics, University of California-Irvine, Irvine, CA 92697, USA.

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http://dx.doi.org/10.1111/j.1749-6632.2008.03609.xDOI Listing
January 2009

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Nat Genet 2007 Mar 18;39(3):319-28. Epub 2007 Feb 18.

Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario L8N 3Z5, Canada.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families. Linkage and copy number variation analyses implicate chromosome 11p12-p13 and neurexins, respectively, among other candidate loci. Neurexins team with previously implicated neuroligins for glutamatergic synaptogenesis, highlighting glutamate-related genes as promising candidates for contributing to ASDs.
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http://dx.doi.org/10.1038/ng1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867008PMC
March 2007

Evaluation of the chromosome 2q37.3 gene CENTG2 as an autism susceptibility gene.

Am J Med Genet B Neuropsychiatr Genet 2005 Jul;136B(1):36-44

Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, 52242, USA.

Autism is a highly heritable neurodevelopmental syndrome with a complex genetic etiology for which no disease genes have yet been definitively identified. We ascertained three subjects with autism spectrum disorders and chromosome 2q37.3 terminal deletions, and refined the deletion breakpoint regions using polymorphism mapping and fluorescence in situ hybridization (FISH) probes. We then genotyped polymorphic markers downstream from the breakpoint region in a sample of autism affected sibling pair families. Both the chromosomal breakpoints and linkage analyses focused our attention on the gene centaurin gamma-2 (CENTG2), an attractive candidate gene based also on its function and pattern of expression. We therefore assessed CENTG2 for its involvement in autism by (1) screening its exons for variants in 199 autistic and 160 non-autistic individuals, and (2) genotyping and assessing intra-genic polymorphisms for linkage and linkage disequilibrium (LD). The exon screen revealed a Ser --> Gly substitution in one proband, an Arg --> Gly substitution in another, and a number of additional variants unique to the autism families. No unique variants were found in the control subjects. The genotyping produced strong evidence for linkage from two intronic polymorphisms, with a maximum two-point HLOD value of 3.96 and a posterior probability of linkage (PPL) of 51%. These results were contradicted, however, by substantially weaker evidence for linkage from multi-point analyses and by no evidence of LD. We conclude, therefore, that 2q37.3 continues to be a region of interest for autism susceptibility, and that CENTG2 is an intriguing candidate gene that merits further scrutiny for its role in autism.
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http://dx.doi.org/10.1002/ajmg.b.30180DOI Listing
July 2005

A case of autism with an interstitial deletion on 4q leading to hemizygosity for genes encoding for glutamine and glycine neurotransmitter receptor sub-units (AMPA 2, GLRA3, GLRB) and neuropeptide receptors NPY1R, NPY5R.

BMC Med Genet 2004 Apr 16;5:10. Epub 2004 Apr 16.

Department of Pediatrics, University of California, Irvine, Irvine, CA, USA.

Background: Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes.

Case Presentation: We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R.

Conclusions: The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism.
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http://dx.doi.org/10.1186/1471-2350-5-10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC411038PMC
April 2004

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.

Am J Med Genet B Neuropsychiatr Genet 2004 Apr;126B(1):46-50

Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

A recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer liability for autism, especially alleles bearing 11 or more CGG repeats (long alleles). The association is consistent across both a case-control and family-based sample. We attempted to replicate their finding using a larger, independent family-based sample from the NIH Collaborative Programs of Excellence in Autism (CPEA) Network. In our data, allele transmissions to individuals with autism versus unaffected individuals are unbiased, both when alleles are classified by repeat length and when they are classified into long/short categories. Because of the apparent linkage of autism to chromosome 7q, particularly related to the development of language, we also evaluate the relationship between Reelin alleles and the age at which autism subjects use their first word or first phrase. Neither is significantly associated with Reelin alleles. Our results are not consistent with a major role for Reelin alleles in liability to autism.
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http://dx.doi.org/10.1002/ajmg.b.20125DOI Listing
April 2004

Mitochondrial dysfunction in autistic patients with 15q inverted duplication.

Ann Neurol 2003 Jun;53(6):801-4

Department of Pediatrics, College of Medicine, University of California, Irvine, CA, USA.

Two autistic children with a chromosome 15q11-q13 inverted duplication are presented. Both had uneventful perinatal courses, normal electroencephalogram and magnetic resonance imaging scans, moderate motor delay, lethargy, severe hypotonia, and modest lactic acidosis. Both had muscle mitochondrial enzyme assays that showed a pronounced mitochondrial hyperproliferation and a partial respiratory chain block most parsimoniously placed at the level of complex III, suggesting candidate gene loci for autism within the critical region may affect pathways influencing mitochondrial function.
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http://dx.doi.org/10.1002/ana.10596DOI Listing
June 2003

No evidence for linkage of liability to autism to HOXA1 in a sample from the CPEA network.

Am J Med Genet 2002 Aug;114(6):667-72

Department of Psychiatry, University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania, USA.

A recent study by Ingram et al. [2000b: Teratology 62:393-405] suggests a (His)73(Arg) polymorphism (A:G) in HOXA1 contributes substantially to a liability for autism. Using 68 individuals diagnosed with Autism Spectrum Disorders, they found a significant dearth of G homozygotes and biased transmission of G alleles from parents to affected offspring, especially from mothers. Because the connection between HOXA1 and liability to autism is compelling, we attempted to replicate their finding using a larger, independent sample from the Collaborative Programs of Excellence in Autism (CPEA) network. In our data, genotype frequencies conform to Hardy-Weinberg equilibrium; allele transmissions meet Mendelian expectations; and there is no obvious sex-biased allele transmission. Based on our sample size, calculations suggest that we would have at least 95% power to detect linkage and association even if the A:G polymorphism were to account for only 1% of the heritability of autism. Therefore, although we cannot exclude the possibility that the samples in the two studies are intrinsically different, our data from our sample argue against a major role for HOXA1 (His)73(Arg) in liability to autism.
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http://dx.doi.org/10.1002/ajmg.10603DOI Listing
August 2002

Presence of large deletions in kindreds with autism.

Am J Hum Genet 2002 Jul 7;71(1):100-15. Epub 2002 Jun 7.

Geriatrics Research Education and Clinical Center, Puget Sound Veterans Affairs Medical Center, University of Washington, Seattle 98108, USA.

Autism is caused, in part, by inheritance of multiple interacting susceptibility alleles. To identify these inherited factors, linkage analysis of multiplex families is being performed on a sample of 105 families with two or more affected sibs. Segregation patterns of short tandem repeat polymorphic markers from four chromosomes revealed null alleles at four marker sites in 12 families that were the result of deletions ranging in size from 5 to >260 kb. In one family, a deletion at marker D7S630 was complex, with two segments deleted (37 kb and 18 kb) and two retained (2,836 bp and 38 bp). Three families had deletions at D7S517, with each family having a different deletion (96 kb, 183 kb, and >69 kb). Another three families had deletions at D8S264, again with each family having a different deletion, ranging in size from <5.9 kb to >260 kb. At a fourth marker, D8S272, a 192-kb deletion was found in five families. Unrelated subjects and additional families without autism were screened for deletions at these four sites. Families screened included 40 families from Centre d'Etude du Polymorphisme Humaine and 28 families affected with learning disabilities. Unrelated samples were 299 elderly control subjects, 121 younger control subjects, and 248 subjects with Alzheimer disease. The deletion allele at D8S272 was found in all populations screened. For the other three sites, no additional deletions were identified in any of the groups without autism. Thus, these deletions appear to be specific to autism kindreds and are potential autism-susceptibility alleles. An alternative hypothesis is that autism-susceptibility alleles elsewhere cause the deletions detected here, possibly by inducing errors during meiosis.
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http://dx.doi.org/10.1086/341291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC384967PMC
July 2002
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