i wasn't joking when i mentioned autism is genetically linked to chromosome 6.9. of course, these studies are not final and conclusive, but they point to a possible breakthrough in dna research linking autism to genetic causes. more r&d funding are being poured into this subject, thanks to results and findings from these independent studies.
Autism links on chromosome 7
Revised DNA sequence homes in on break points.
Hannah Hoag
View attachment 53651
A revamp of chromosome 7's DNA sequence has brought to light genes associated with autism, several leukaemias and lymphomas
1.
Geneticist Stephen Scherer, of the University of Toronto, and his colleagues identified the site of more than 100 new mutations linked to genetic disorders after studying the genetic makeup of more than 300 new patients and reviewing 1,570 published studies.
Doctors will be able to log onto a new dynamic database in which the sequence anomalies are held, and determine whether a patient's genetic make-up matches those of others. As information is added to the free-access database, more mutations may stand out. "It's a quick way to identify candidate genes for a disorder," Scherer says.
Some of the mutations seen in patients with autism have turned up in genes related to speech and communication, others are close to genes that enable neurons to communicate.
“A single gene change doesn't seem to be sufficient in most families”
The genetics of autism is complex, warns Beth Rosen-Sheidley of the Tufts-New England Medical Center in Boston. "A single gene change doesn't seem to be sufficient in most families." Any test for the disease would be difficult to interpret, she says. "It's a bit of a quagmire. One marker for the disease might increase the risk, but by how much?"
To produce a precise map, Scherer's team started with the draft chromosome 7 sequence published by the private company Celera Genomics
2. They then filled in many of the gaps with data from the international public consortium
3.
The researchers admit that the resulting sequence is not completely finished, but reckon that it is in good shape. Others feel, however, that it has some way to go.
https://www.nature.com/news/2003/030407/full/news030407-10.html
Identification of Chromosome 7 Inversion Breakpoints in an Autistic Family Narrows Candidate Region for Autism Susceptibility
Abstract
Chromosomal breaks and rearrangements have been observed in conjunction with autism and autistic spectrum disorders. A chromosomal inversion has been previously reported in autistic siblings, spanning the region from approximately 7q22.1 to 7q31. This family is distinguished by having multiple individuals with autism and associated disabilities. The region containing the inversion has been strongly implicated in autism by multiple linkage studies, and has been particularly associated with language defects in autism as well as in other disorders with language components. Mapping of the inversion breakpoints by FISH has localized the inversion to the region spanning approximately 99–108.75Mb of chromosome 7. The proximal breakpoint has the potential to disrupt either the coding sequence or regulatory regions of a number of cytochrome P450 genes while the distal region falls in a relative gene desert. Copy number variant analysis of the breakpoint regions detected no duplication or deletion that could clearly be associated with disease status. Association analysis in our autism data set using single nucleotide polymorphisms located near the breakpoints showed no significant association with proximal breakpoint markers, but has identified markers near the distal breakpoint (~108–110Mb) with significant associations to autism. The chromosomal abnormality in this family strengthens the case for an autism susceptibility gene in the chromosome 7q22-31 region and targets a candidate region for further investigation.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441209/
CHROMOSOME 7
Individuals who carry an extra copy of 7q11.23, the genetic region on
chromosome 7 that is missing in those with
Williams syndrome, have language impairments and other autism-like social difficulties.
Relevance to autism:
Although deletion of 7q11.23 leads to
Williams syndrome, duplication of the region resembles autism. Of 14 children with 7q11.23 duplication syndrome, all
have problems speaking, 7 have mild or moderate mental retardation, and 6 have either been formally diagnosed with autism or have autism-like features, such as poor eye contact or trouble with social interactions
1.
GTF21, a gene within the 7q11.23 region, interacts with DLX5 and DLX6 — transcription factors implicated in autism
2.
Other autism-implicated genes on chromosome 7 include
AUTS2,
CNTNAP2 and
FOXP2. AUTS2 has been linked to autism in various gene association studies
3.
A 2010 study shows that a variant of CNTNAP2
may alter the brain to emphasize connections between nearby regions and diminish those between more distant ones
4.
Variants in CNTNAP2 also affect the
timing of language development in the general population
5.
FOXP2 is linked to language development and
regulates CNTNAP2 gene expression.
Williams syndrome:
Deletion of the 7q11.2 region leads to the autism-related disorder,
Williams syndrome. Children with Williams syndrome have a range of cognitive symptoms, including a happy and highly social demeanor, developmental delay and strong language skills. They also have cardiovascular symptoms and facial
dysmorphology, such as a small nose with a flattened bridge and a small chin
6.
GTF2I is one of a handful of genes that researchers consider to be key players in
Williams syndrome. The protein it encodes is a transcription factor, affecting the expression of other genes, but its precise role is unknown
7.
One child with Williams syndrome lacks one copy of all the genes on the 7q11.2 region
except for GTF21, for which she has two functional copies. The girl has facial features characteristic of Williams syndrome and a heart defect, but no developmental delay. By the time the girl was 2 years old, her caretakers confirmed that she has normal social behavior: She is shy around strangers and doesn’t stare at other people’s eyes.
https://www.spectrumnews.org/wiki/chromosome-7/
Gene on Chromosome 7 Associated With Autism : Three studies show that the integrity of neuroligin-neurexin axis is critical for normal development.
Publish date: February 1, 2008
By
Mary Ann Moon
Three independent studies implicate the CNTNAP2 gene on chromosome 7 as an autism-susceptibility gene, researchers reported.
The three studies used different strategies to examine the possible genetic basis for autism, and all independently arrived at the same conclusion: Variations–some common and some rare–in the CNTNAP2 gene predispose carriers to autism.
“It will be important to begin to characterize the genotype-phenotype correlations across this gene so that we may begin to use CNTNAP2 as a diagnostic and prognostic tool,” Dr. Dietrich A. Stephan said in an editorial comment accompanying the three reports (Am. J. Hum. Genet. 2008;82:7-9).
“These preliminary findings lead one to speculate whether early detection of CNTNAP2 mutation carriers, coupled with early intervention, could coax children through a critical period in development (12-24 months of age) and allow them to emerge undamaged and continue to develop normally thereafter,” said Dr. Stephan of the Translational Genomics Research Institute, Phoenix.
In the first study, Maricela Alarcón, Ph.D., of the University of California, Los Angeles, Center for Autism Research and Treatment and her associates built on their previous finding linking a region of chromosome 7q35 that contains approximately 200 known genes with language deficits and autism spectrum disorders. They first genotyped the region in 172 parent-child trios from the Autism Genetics Research Exchange database on 2,758 single nucleotide polymorphisms. This narrowed the search to four likely candidate genes, including CNTNAP2.
This gene was already suspected of being involved in autism since it is a member of the neurexin superfamily; in case studies, mutations in these genes have been linked to severe autism, temporal lobe seizures, language regression, and repetitive behaviors.
The researchers then tested a different set of 304 parent-child trios and confirmed that only the CNTNAP2 gene significantly correlated with a delay in language acquisition–specifically, the age at which carriers used their first word. The investigators then identified a rare microdeletion within CNTNAP2 that was present in an autistic child and his father but not in 1,000 control chromosomes.
Dr. Alarcón and her associates also examined regional gene expression in human fetal brains, and found that CNTNAP2 was highly restricted to areas “known to contribute to complex human behaviors including speech and language, reward, frontal executive function, as well as joint attention, a core deficit in autism spectrum disorders.”
“Our demonstration of the developmental expression of CNTNAP2 being confined to brain circuitry known to be disrupted in autism spectrum disorders provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder,” the investigators noted (Am. J. Hum. Genet. 2008;82:150-9).
In the second study, Dan E. Arking, Ph.D., of Johns Hopkins University, Baltimore, and his associates genotyped 72 families with multiple affected children in the National Institute of Mental Health Autism Genetics Initiative database.
They confined their analysis to the most strict phenotypic inclusion criteria ever used in a sample of that size, “which allowed [the] subtle association to be detected without genomewide background noise,” Dr. Stephan said.
Dr. Arking and his associates identified one common single nucleotide polymorphism, rs7794745, in the CNTNAP2 gene that was significantly associated with autism. They then confirmed the finding by genotyping a separate sample of 1,295 parent-child trios from the database. The researchers also found that transmission frequency was significantly greater from mothers than from fathers.
“It is likely that additional genetic variants in this gene that contribute to autism susceptibility remain to be discovered,” Dr. Arking and his associates said (Am. J. Hum. Genet. 2008;82:160-4).
In the third study, Dr. Betul Bakkaloglu of Yale University, New Haven, Conn., and associates mapped balanced rearrangements in children who had social and cognitive delays “as a means of identifying candidate genes that may harbor rare disease alleles.” They found an inversion of chromosome 7 in a mentally retarded child with autistic features, and further analysis showed disruption in the CNTNAP2 gene at 7q35.
Dr. Bakkaloglu and associates then resequenced all 24 exons of CNTNAP2 in a sample of 635 subjects with autism spectrum disorders and 942 controls. They found eight rare variants predicted to have an adverse effect on the gene's function. These variants occurred twice as often in affected subjects as in controls.
One particular deleterious variant, I869T, was found in four autistic children from three different families, but was not present in more than 4,000 chromosomes assessed in controls, Dr. Bakkaloglu and associates said (Am. J. Hum. Genet. 2008;82:165-73).
“Now that we have definitive evidence from several perspectives that integrity of the neuroligin-neurexin axis is critical for normal development, we must launch into a candidate gene-resequencing effort to fully describe mutations in the other members of these gene families in autism spectrum disorders,” Dr. Stephan noted.
https://www.mdedge.com/psychiatry/a...ssociated-autism-three-studies-show-integrity
