The same gene family that may have helped the human brain become larger and more complex than in any other animal also is linked to the severity of autism, according to new research from the University of Colorado Anschutz Medical Campus.
The gene family is made up of over 270 copies of a segment of DNA called DUF1220. DUF1220 codes for a protein domain – a specific functionally important segment within a protein. The more copies of a specific DUF1220 subtype a person with autism has, the more severe the symptoms, according to a paper.
This association of increasing copy number (dosage) of a gene-coding segment of DNA with increasing severity of autism is a first and suggests a focus for future research into the condition Autism Spectrum Disorder (ASD). ASD is a common behaviourally defined condition whose symptoms can vary widely – that is why the word ‘spectrum’ is part of the name. One federal study showed that ASD affects one in 88 children.
‘Previously, we linked increasing DUF1220 dosage with the evolutionary expansion of the human brain,’ says James Sikela, PhD, a professor in the Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine. Sikela led the autism study which also involved other members of his laboratory.

‘One of the most well-established characteristics of autism is an abnormally rapid brain growth that occurs over the first few years of life. That feature fits very well with our previous work linking more copies of DUF1220 with increasing brain size. This suggests that more copies of DUF1220 may be helpful in certain situations but harmful in others.’

The research team found that not only was DUF1220 linked to severity of autism overall, they found that as DUF1220 copy number increased, the severity of each of three main symptoms of the disorder — social deficits, communicative impairments and repetitive behaviours – became progressively worse.
In 2012, Sikela was the lead scientist of a multi-university team whose research established the link between DUF1220 and the rapid evolutionary expansion of the human brain. The work also implicated DUF1220 copy number in brain size both in normal populations as well as in microcephaly and macrocephaly (diseases involving brain size abnormalities).

Jack Davis, PhD, who contributed to the project while a postdoctoral fellow in the Sikela lab, has a son with autism and thus had a very personal motivation to seek out the genetic factors that cause autism.

The research by Sikela, Davis and colleagues at the Anschutz campus in Aurora, Colo., focused on the presence of DUF1220 in 170 people with autism.
Strikingly, Davis says, DUF1220 is as common in people who do not have ASD as in people who do. So the link with severity is only in people who have the disorder.

‘Something else is at work here, a contributing factor that is needed for ASD to manifest itself,’ Davis says. ‘We were only able to look at one of the six different subtypes of DUF1220 in this study, so we are eager to look at whether the other subtypes are playing a role in ASD.’
Because of the high number of copies of DUF1220 in the human genome, the domain has been difficult to measure. As Sikela says, ‘To our knowledge DUF1220 copy number has not been directly examined in previous studies of the genetics of autism and other complex human diseases .So the linking of DUF1220 with ASD is also confirmation that there are key parts of the human genome that are still unexamined but are important to human disease.’ University of Colorado Denver

In light of new research, Dr André Lacroix suggests genetic screening to find ‘silent carriers’.
Genetic research suggests to Dr. André Lacroix, professor at the University of Montreal, that clinicians’ understanding and treatment of a form of Cushing’s syndrome affecting both adrenal glands will be fundamentally changed, and that moreover, it might be appropriate to begin screening for the genetic mutations that cause this form of the disease. ‘Screening family members of bilateral adrenal Cushing’s syndrome patients with genetic mutations may identify affected silent carriers,’ Lacroix said ‘The development of drugs that interrupt the defective genetic chemical link that causes the syndrome could, if confirmed to be effective in people, provide individualised specific therapies for hypercortisolism, eliminate the current practice of removing both adrenal glands, and possibly prevent disease progression in genetically affected family members.’ Adrenal glands sit above the kidneys are mainly responsible for releasing cortisol, a stress hormone. Hypercortiolism means a high level of the adrenal hormone cortisol, which causes many symptoms including weight gain, high blood pressure, diabetes, osteoporosis, concentration deficit and increased cardiovascular deaths.

Cushing’s syndrome can be caused by corticosteroid use (such as for asthma or arthritis), a tumour on the adrenal glands, or a pituitary gland that releases too much ACTH. The pituitary gland sits under the brain and releases various hormones that regulate our bodies’ mechanisms.

Jérôme Bertherat is a researcher at Cochin Hospital in Paris. In the study he showed that 55% of Cushing’s Syndrome patients with bilaterally very enlarged adrenal glands have mutations in a gene that predisposes to the development of adrenal tumours. This means that bilateral adrenal Cushing’s is much more hereditary than previously thought. The new knowledge will also enable clinicians to undertake genetic screening. Hervé Lefebvre is a researcher at the University Hospital in Rouen, France. His research shows that the adrenal glands from the same type of patients with two large adrenal glands can produce ACTH, which is normally produced by the pituitary gland. Hormone receptors are the chemical link that cause a cell to behave differently when a hormone is present. Several misplaced hormone receptors cause the ACTH to be produced in the enlarged benign adrenal tissue. Knowing this means that researchers might be able to develop drugs that interrupt the receptors for these hormones and possibly even prevent the benign tissue from developing in the first place. Université de Montréal.

Cancer researchers led by stem cell scientist Dr. John Dick have discovered a pre-leukemic stem cell that may be the first step in initiating disease and also the culprit that evades therapy and triggers relapse in patients with acute myeloid leukaemia (AML).
The research​ is a significant leap in understanding the steps that a normal cell has to go through as it turns into AML, says Dr. Dick, and sets the stage to advance personalised cancer medicine by potentially identifying individuals who might benefit from targeting the pre-leukemic stem cell. AML is an aggressive blood cancer that the new research shows starts in stem cells in the bone marrow. Dr. Dick, a Senior Scientist at Princess Margaret Cancer Centre, University Health Network (UHN), and Professor in the Department of Molecular Genetics, University of Toronto, pioneered the cancer stem cell field by first identifying leukaemia stem cells (1994) and colon cancer stem cells (2007).
‘Our discovery lays the groundwork to detect and target the pre-leukemic stem cell and thereby potentially stop the disease at a very early stage when it may be more amenable to treatment,’ says Dr. Dick, who holds a Canada Research Chair in Stem Cell Biology and is also Director of the Cancer Stem Cell Program at the Ontario Institute for Cancer Research (OICR).
‘Now we have a potential tool for earlier diagnosis that may allow early intervention before the development of full AML. We can also monitor remission and initiate therapy to target the pre-leukemic stem cell to prevent relapse,’ he says.
The findings show that in about 25% of AML patients, a mutation in the gene DNMT3a causes pre-leukemic stem cells to develop that function like normal blood stem cells but grow abnormally. These cells survive chemotherapy and can be found in the bone marrow at remission, forming a reservoir of cells that may eventually acquire additional mutations, leading to relapse.
The discovery of pre-leukemic stem cells came out of a large Leukemia Disease Team that Dr. Dick assembled and included oncologists who collected samples for the Princess Margaret Cancer Centre Biobank and genome scientists at the OICR who developed sophisticated targeted sequencing methodology. With this team, it was possible to carry out genomic analysis of more than 100 leukaemia genes on many patient samples. The findings also capitalised on data from more than six years of experiments in Dr. Dick’s lab involving growing human AML in special mice that do not reject human cells.
‘By peering into the black box of how cancer develops during the months and years prior to when it is first diagnosed, we have demonstrated a unique finding. People tend to think relapse after remission means chemotherapy didn’t kill all the cancer cells. Our study suggests that in some cases the chemotherapy does, in fact, eradicate AML; what it does not touch are the pre-leukemic stem cells that can trigger another round of AML development and ultimately disease relapse,’ says Dr. Dick, who anticipates the findings will spawn accelerated drug development to specifically target DNMT3a.
These findings should also provide impetus for researchers to look for pre-cancerous cells in AML patients with other mutations and even in non-blood cancers. Princess Margaret Cancer Centre, University Health Network

Researchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease. Yale University

A study done by researchers at Fox Chase Cancer Center shows that many relatives of patients who undergo testing for a gene linked to breast and ovarian cancers misinterpret the results, and less than half of those who could benefit from genetic testing say they plan to get tested themselves—despite the fact that knowing your genetic status may help catch the disease in its earliest stages.
‘People don’t always understand genetic information, so there’s confusion,’ says study author Mary B. Daly, MD, PhD, chair of the Department of Clinical Genetics at Fox Chase. ‘Family members are either not understanding what they’re hearing, not realising it has implications for them, or they’re not hearing it at all.’
For a long time, Daly says she ‘naively’ assumed that, once one family member knew whether or not they carried genes linked to breast and ovarian cancers—known as BRCA1/2—their entire family would understand the result, and what it meant for their own genetic risk. ‘Over time, we realised that wasn’t happening, or it wasn’t happening very well.’
Some genetic information is straightforward, says Daly. For example, when a woman learns she carries BRCA1/2 that means her parents, siblings and children may also carry the gene. But there are more ‘indeterminate’ results, which are harder to interpret, she adds. If a woman with a strong family history of breast and ovarian cancers tests negative for the BRCA1/2 genes, that does not mean her relatives are not at risk, says Daly—her siblings could still carry the gene, or there could be additional genes present that predispose them to cancer that clinicians don’t yet know how to test for.
‘When you look at some of these families who are so full of breast and ovarian cancer, and the person tests negative, you think there’s got to be something going on here. We just can’t find it. That’s a difficult thing for someone to explain to a relative,’ says Daly.
To understand better what was (and was not) being communicated after people underwent genetic testing, Daly and her team called 438 relatives of 253 people who had undergone genetic testing and said they’d shared their results. More than one-quarter of family members reported the test result incorrectly. They were most likely to understand positive results—like their family member carries the BRCA1/2 gene. But only 60% understood the so-called ‘indeterminate’ results, where their relative tested negative for the gene but they and other family members could still be at risk. Nearly one-third said they had trouble understanding the result.
Concerningly, only half (52%) of family members whose relative tested positive for the BRCA1/2 gene said they planned to get tested themselves. Among those whose relative tested negative for the BRCA1/2 gene, but knew the gene was present in their families (meaning they could still carry the gene), only 36% said they were going to find out their own genetic risk. ‘These findings imply the family members did not fully understand the significance of these results for their own risk,’ says Daly.
People were more likely to share their results with adult children than parents or siblings, and particularly with female relatives. ‘Over and over you hear people say ‘I’m doing this for my children’s sake,” says Daly.
As part of the study, Daly and her colleagues had asked half of the people getting tested to participate in two coaching sessions to help them communicate their results to relatives, such as through role playing. However, these people were no more likely to communicate the result of their tests than people who had simply sat through educational sessions about overall health. ‘It didn’t matter which group they were in, unfortunately,’ says Daly. ‘That disappointed me.’
But it also inspired her to develop the next project—exploring the effect of directly reaching out to the relatives of someone who underwent genetic testing (with that person’s permission), to see if hearing the results from an expert who’s not personally involved in the situation helps family members understand what they mean. Fox Chase Cancer Center