Genetics for
Mental Health Professionals
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What Is Autism?
Autism is a brain disorder that limits a person's ability to communicate and relate to other people. It first appears in young children, who fall along a spectrum from mild to severe. Some people can navigate their world, some have exceptional abilities, while others struggle to speak. Autism spectrum disorders (ASDs) affect about one child in 68, striking nearly five times as many boys as girls.
How Does Autism Affect the Brain?
Autism affects parts of the brain that control emotions, communication, and body movements. By the toddler years, some children with ASDs have unusually large heads and brains -- which may be because of problems with brain growth. Abnormal genes, passed down through a family, have been linked to poor functions in some parts of the brain. Researchers hope to find a way to diagnose autism through brain scans.
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1999 Autism Study Looked at Chromosome 15
In 1999, researchers examined a series of 127 children diagnosed with autistic disorder the karyotypes of 8, on whom data were available, showed the following chromosomal abnormalities:
- breakage
- a 47 XY pattern: 47 XY +der (15) (pter q15: p11 pter), 47 XXY and 46 XY, inv (2) (p1 1:q13pat, 3q+)
- trisomy 13
- inversion-duplication of chromosome 15
Compared to those who were not karyotyped or had normal karyotypes, the children with abnormalities, although cognitively more delayed, were not rated as more severely autistic
Facial dysmorphias and minor physical anomalies tended to be more frequent in the chromosomally deviant subgroup
No differences in demographic characteristics or parental ages were evident
Results were consistent with the view of variability of expression of marker chromosome deviations and a greater severity of retardation and symptoms of autism in those affected
Konstantareas, M., & Homatidis, S. S. (1999). Chromosomal abnormalities in a series of children with autistic disorder. Journal Of Autism & Developmental Disorders, 29(4), 275.
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Autism Study looked at Chromosome 7
In 2001, Gutknecht found that:
Although his findings must be considered with caution because LOD scores (Method of Estimating Linkage Distances) values did not reach the threshold for significant linkage:
a region of approximately 50 cM on the long arm of chromosome 7 appears to play a role in the etiology of autistic disorder.
Gutknecht, L. (2001). Full-Genome scans with autistic disorder: A review. Behavior Genetics, 31(1), 113-123.
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Autism Study looked at Chromosomes 2, 7, 15, X
In 2001 after reviewing the research on the genetics of Autism, Folstein & Rosen-Sheidley found that on the basis of decades of research, genetic factors have clearly emerged as the most significant etiology for autism spectrum disorder
Although there are numerous case reports of cytogenetic abnormalities and associations with specific Mendelian disorders, most cases are idiopathic and apparently due to complex inheritance patterns
This had made the identification of susceptibility genes difficult
Nevertheless, considerable progress has been made in identifying chromosomal regions of interest for some of the genes involved, particularly on chromosomes:
Folstein, S. E., & Rosen-Sheidley, B. (2001). Genetics of autism: Complex aetiology for a heterogeneous disorder. Nature Reviews Genetics, 2(12), 943-955. doi:10.1038/35103559
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Autism Study looked at X-linked genes
Researchers in 2003 concluded that after examining cases with mutations in two X-linked genes encoding neuroligins NLGN3 and NLGN4 in siblings with autism-spectrum disorders.
These mutations affect cell-adhesion molecules localized at the synapse and suggest that a defect of synaptogenesis may predispose to autism
Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I., & ... Philippe, A. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34(1), 27.
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Autism Study examined Family Relatedness
Yirmiya & Shadek (2005) did a meta-analysis of 17 studies in which the psychiatric difficulties of parents of individuals with autism were compared to the psychiatric difficulties of other groups of parents.
The overall group comparison revealed a significant difference of low magnitude. They explored six potential moderator variables. A notable contribution of the current meta-analysis comprises its identification of the moderator variable of ‘type of comparison group’, which highlights the importance of the comparison group to which researchers compare parents of individuals with autism.
Parents of individuals with autism demonstrated more psychiatric difficulties than did three other parent groups:
1.parents of typically developing individuals
2.parents of individuals with Down Syndrome
3.parents of individuals with Mental Retardation of unknown etiology
Parents of individuals with autism actually revealed significantly fewer psychiatric difficulties compared to parents of individuals with Learning Disabilities, and compared to parents of children with psychiatric disorders
Yirmiya, N., & Shaked, M. (2005). Psychiatric disorders in parents of children with autism: a meta-analysis. Journal Of Child Psychology & Psychiatry, 46(1), 69-83. doi:10.1111/j.1469-7610.2004.00334.x
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Another Autism Study looked at Family Relatedness
Also in 2005, Lauritsen et al found that the highest risk of autism was found in families with a history of autism, or Asperger‘s syndrome and other Pervasive Developmental Delays (PDDs) in siblings, supporting the commonly accepted knowledge that genetic factors are involved in the etiology of autism
Lauritsen, M., Pedersen, C., & Mortensen, P. (2005). Effects of familial risk factors and place of birth on the risk of autism: a nationwide register-based study. Journal Of Child Psychology & Psychiatry, 46(9), 963-971. doi:10.1111/j.1469-7610.2004.00391.x
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Autism Study examined Genomic Imprinting
Badcock & Crespi in 2006 proposed hypothesis of imbalanced genomic imprinting as supported by:
1.strong genomic-imprinting component to the genetic and developmental mechanisms of autism, Angelman syndrome, Rett syndrome and Turner syndrome
2.core behavioral features of autism, such as self-focused behavior, altered social interactions and language, and enhanced spatial and mechanistic cognition abilities
3.degree to which relevant brain functions and structures are altered in autism and related disorders
The imprinted brain theory of autism has important implications for understanding the genetic, epigenetic, neurological and cognitive bases of autism, as ultimately due to imbalances in the outcomes of intragenomic conflict between effects of maternally vs. paternally expressed genes
Badcock, C. C., & Crespi, B. B. (2006). Imbalanced genomic imprinting in brain development: an evolutionary basis for the aetiology of autism. Journal Of Evolutionary Biology, 19(4), 1007-1032. doi:10.1111/j.1420-9101.2006.01091.x
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Autism Study examined Family Risk Factors
In 2007 Familial history risk factors in relation to autism were examined in a cohort of 164 autistic children referred to The Autism Center at New Jersey Medical School—University of Medicine and Dentistry of New Jersey, Newark, over a 2-year period (2001-2003).
Information related to familial history was obtained from each family and reviewed by a clinician.
It is shown that
1.these families carry a higher overall burden of psychiatric and developmental illnesses compared to reported national levels
2.These families also carry a relatively high incidence of medical disorders, independently of developmental and psychiatric disorders
3.This work supported the underlying presence of genetic factors in the etiology of autism
Brimacombe, M., Xue, M., & Parikh, A. (2007). Familial Risk Factors in Autism. Journal
Of Child Neurology, 22(5), 593-597.
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Autism Study examined DRD3 Gene
In 2009, researcher concluded that the DRD3 gene is related to stereotyped behavior, liability to side effects of antipsychotic medication, and movement disorders and may therefore have important clinical implications for Autism Spectrum Disorder
de Krom, M., Staal, W. G., Ophoff, R. A., Hendriks, J., Buitelaar, J., Franke, B., & ... van Ree, J. M. (2009). A common variant in DRD3 receptor is associated with autism spectrum disorder. Biological Psychiatry, 65(7), 625-630. doi:10.1016/j.biopsych.2008.09.035
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Autism Study examined Chromosome 7 (AUTS 1) & 2 (AUTS 5)
In 2010, Researchers performed a high-density association analysis in AUTS1 and AUTS5, testing more than 3000 single nucleotide polymorphisms (SNPs) in all known genes in each region, as well as SNPs in non-genic highly conserved sequences.
SNP genotype data were also used to investigate copy number variation within these regions.
Researchers looked at a study sample which consisted of 127 and 126 families, showing linkage to the AUTS1 and AUTS5 regions, respectively, and 188 gender-matched controls
Further investigation of the strongest association results was conducted in an independent European family sample containing 390 affected individuals.
Association and copy number variant analysis highlighted several genes that warrant further investigation, including IMMP2L and DOCK4 on chromosome 7
Maestrini, E. E., Pagnamenta, A. T., Lamb, J. A., Bacchelli, E. E., Sykes, N. H., Sousa, I. I., & ... Minderaa, R. B. (2010). High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility. Molecular Psychiatry, 15(9), 954-968. doi:10.1038/mp.2009.34
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Autism Study examined PHF8 and WNK3 Genes
In 2011 Baniaga discovered findings that suggest a number of genes involved in neurodevelopment as well as craniofacial and systemic features that may account for the observed phenotypes in the nine affected patients with Autism.
Among the candidate genes found
1.CYFIP1 gene, which is involved in maturation and maintenance of dendrites
2.Gamma acid receptor family (GABA) which exhibit linkage disequilibrium with autistic disorders
3.PHF8 and WNK3 genes, which have been shown to be associated with X-linked mental retardation (XLMR), present the most interesting findings as they may account for most of the neurodevelopmental pathogenesis observed in the affected patients
Future studies need to be conducted in order to precisely determine the networks these genes participate in and how they are regulated to gain a deeper understanding in the roles they play in the clinical presentations of affected individuals with ASDs.
Baniaga, A. (2011). Pathogenic copy number variants (pCNVs) in individuals diagnosed on the autism spectrum disorder (ASD): A closer look at candidate genes. Mcgill Science Undergraduate Research Journal, 6(1), 15-22.
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AUTISM GENETIC STUDY REFERENCES
Badcock, C. C., & Crespi, B. B. (2006). Imbalanced genomic imprinting in brain
development: an evolutionary basis for the aetiology of autism. Journal Of Evolutionary Biology, 19(4), 1007-1032. doi:10.1111/j.1420-9101.2006.01091.x
Baniaga, A. (2011). Pathogenic copy number variants (pCNVs) in individuals diagnosed
on the autism spectrum disorder (ASD): A closer look at candidate genes. Mcgill Science Undergraduate Research Journal, 6(1), 15-22.
Brimacombe, M., Xue, M., & Parikh, A. (2007). Familial Risk Factors in Autism. Journal
Of Child Neurology, 22(5), 593-597.
de Krom, M., Staal, W. G., Ophoff, R. A., Hendriks, J., Buitelaar, J., Franke, B., & ... van
Ree, J. M. (2009). A common variant in DRD3 receptor is associated with autism spectrum disorder. Biological Psychiatry, 65(7), 625-630. doi:10.1016/j.biopsych.2008.09.035
Folstein, S. E., & Rosen-Sheidley, B. (2001). Genetics of autism: Complex aetiology for
a heterogeneous disorder. Nature Reviews Genetics, 2(12), 943-955. doi:10.1038/35103559
Gutknecht, L. (2001). Full-Genome scans with autistic disorder: A review. Behavior
Genetics, 31(1), 113-123.
Jamain, S., Quach, H., Betancur, C., Rastam, M., Colineaux, C., Gillberg, I., & ...
Philippe, A. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34(1), 27.
Konstantareas, M., & Homatidis, S. S. (1999). Chromosomal abnormalities in a series of
children with autistic disorder. Journal Of Autism & Developmental Disorders, 29(4), 275.
Lauritsen, M., Pedersen, C., & Mortensen, P. (2005). Effects of familial risk factors and
place of birth on the risk of autism: a nationwide register-based study. Journal Of Child Psychology & Psychiatry, 46(9), 963-971. doi:10.1111/j.1469-7610.2004.00391.x
Maestrini, E. E., Pagnamenta, A. T., Lamb, J. A., Bacchelli, E. E., Sykes, N. H., Sousa,
I. I., & ... Minderaa, R. B. (2010). High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L–DOCK4 gene region in autism susceptibility. Molecular Psychiatry, 15(9), 954-968. doi:10.1038/mp.2009.34
Yirmiya, N., & Shaked, M. (2005). Psychiatric disorders in parents of children with
autism: a meta-analysis. Journal Of Child Psychology & Psychiatry, 46(1), 69-83. doi:10.1111/j.1469-7610.2004.00334.x
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