A collaborative team of researchers has used next generation sequencing to identify clinically relevant genetic variants associated with a rare pediatric speech disorder.
Childhood apraxia of speech (CAS) is a rare, severe speech disorder that in some patients also affects cognitive, language, and learning processes.

In this study, Elizabeth Worthey, PhD, assistant professor of paediatrics (genomic paediatrics and bioinformatics) at the Medical College of Wisconsin, working with Dr. Lawrence Shriberg at the Waisman Center, University of Wisconsin – Madison and their colleagues used whole exome sequencing to search for variants associated with CAS.

Prior studies have identified a few genes associated with CAS. In this study, ten pediatric patients were sequenced, and in eight of the cases, clinically significant variants associated with CAS were identified. In some cases patients were found to have apparently deleterious variants in more than one gene. The findings both confirmed previous reports of candidate causal genes and identified novel candidate associations.

‘This study exemplifies the potential productivity of whole exome sequencing for complex neurodevelopmental disorders such as CAS. The current list price to test individual genes is far in excess of the cost of whole exome, and it is also more time effective to perform these tests concurrently rather than looking at one gene at a time,’ said Dr. Worthey. ‘It is likely that a significant proportion of patients with complex phenotypes will be found to have deleterious variants in multiple genes; single gene testing would be unlikely to identify such cases.’ Medical College of Wisconsin

Scientists at the National Cancer Institute (NCI) have generated a data set of cancer-specific genetic variations and are making these data available to the research community.
This will help cancer researchers better understand drug response and resistance to cancer treatments.
‘To date, this is the largest database worldwide, containing 6 billion data points that connect drugs with genomic variants for the whole human genome across cell lines from nine tissues of origin, including breast, ovary, prostate, colon, lung, kidney, brain, blood, and skin,’ said Yves Pommier, M.D., Ph.D., chief of the Laboratory of Molecular Pharmacology at the NCI in Bethesda, Md., in an interview. ‘We are making this data set public for the greater community to use and analyse.
‘Opening this extensive data set to researchers will expand our knowledge and understanding of tumorigenesis [the process by which normal cells are transformed into cancer], as more and more cancer-related gene aberrations are discovered,’ Pommier added. ‘This comes at a great time, because genomic medicine is becoming a reality, and I am very hopeful this valuable information will change the way we use drugs for precision medicine.’
Pommier and colleagues conducted whole-exome sequencing of the NCI-60 human cancer cell line panel, which is a collection of 60 human cancer cell lines, and generated a comprehensive list of cancer-specific genetic variations. Preliminary studies conducted by the researchers indicate that the extensive data set has the potential to dramatically enhance understanding of the relationships between specific cancer-related genetic variations and drug response, which will accelerate the drug development process.
The NCI-60 human cancer cell line panel is used extensively by cancer researchers to discover novel anti-cancer drugs. To conduct whole-exome sequencing, Pommier and his NCI team extracted DNA from the 60 different cell lines, which represent cancers of the lung, colon, brain, ovary, breast, prostate, and kidney, as well as leukaemia and melanoma, and catalogued the genetic coding variants for the entire human genome. The genetic variations identified were of two types: type I variants corresponding to variants found in the normal population, and type II variants, which are cancer-specific.
The researchers then used the Super Learner algorithm to predict the sensitivity of cells harboring type II variants to 103 anti-cancer drugs approved by the FDA and an additional 207 investigational new drugs. They were able to study the correlations between key cancer-related genes and clinically relevant anti-cancer drugs, and predict the outcome.

The data generated in this study provide means to identify new determinants of response and mechanisms of resistance to drugs, and offer opportunities to target genomic defects and overcome acquired resistance, according to Pommier. To enable this, the researchers are making these data available to all researchers via two database portals, called the CellMiner database and the Ingenuity systems database. American Association for Cancer Research

One night when she was trying to fall asleep, a 60-year-old woman suddenly began hearing music, as if a radio were playing at the back of her head.

The songs were popular tunes her husband recognised when she sang or hummed them. But she herself could not identify them.

This is the first known case of a patient hallucinating music that was familiar to people around her, but that she herself did not recognise, according to Dr. Danilo Vitorovic and Dr. José Biller of Loyola University Medical Center.

The case raises ‘intriguing questions regarding memory, forgetting and access to lost memories,’ the authors write.

Musical hallucinations are a form of auditory hallucinations, in which patients hear songs, instrumental music or tunes, even though no such music is actually playing. Most patients realise they are hallucinating, and find the music intrusive and occasionally unpleasant. There is no cure.

Musical hallucinations usually occur in older people. Several conditions are possible causes or predisposing factors, including hearing impairment, brain damage, epilepsy, intoxications and psychiatric disorders such as depression, schizophrenia and obsessive-compulsive disorder. Hearing impairment is the most common predisposing condition, but is not by itself sufficient to cause hallucinations.

Vitorovic and Biller describe a hearing-impaired patient who initially hallucinated music when she was trying to fall asleep. Within four months, she was hearing music all the time. For example, she would hear one song over and over for three weeks, then another song would begin playing. The volume never changed, and she was able to hear and follow conversations while hallucinating the music.

The patient was treated with carbamazepine, an anti-seizure drug, and experienced some improvement in her symptoms.

The unique feature of the patient was her ability to hum parts of some tunes and recall bits of lyrics from some songs that she did not even recognise. This raises the possibility that the songs were buried in her memory, but she could not access them except when she was hallucinating.

‘Further research is necessary on the mechanisms of forgetfulness,’ Vitorovic and Biller write. ‘In other words, is forgotten information lost, or just not accessible?’

Vitorovic is a former chief neurology resident and Biller is a professor and chair in the Department of Neurology of Loyola University Chicago Stritch School of Medicine. Loyola University Health System

Genes have an influence on whether we are left handed or right handed.

A genetic study has identified a biological process that influences whether we are right handed or left handed.
Scientists at the Universities of Oxford, St Andrews, Bristol and the Max Plank Institute in Nijmegen, the Netherlands, found correlations between handedness and a network of genes involved in establishing left-right asymmetry in developing embryos.
‘The genes are involved in the biological process through which an early embryo moves on from being a round ball of cells and becomes a growing organism with an established left and right side,’ explained first author William Brandler, a PhD student in the MRC Functional Genomics Unit at Oxford University.
The researchers suggest that the genes may also help establish left-right differences in the brain, which in turn influences handedness.
Humans are the only species to show such a strong bias in handedness, with around 90% of people being right-handed. The cause of this bias remains largely a mystery.
The researchers, led by Dr Silvia Paracchini at the University of St Andrews, were interested in understanding which genes might have an influence on handedness, in order to gain an insight into the causes and evolution of handedness.
The team carried out a genome-wide association study to identify any common gene variants that might correlate with which hand people prefer using.
The most strongly associated, statistically significant variant with handedness is located in the gene PCSK6, which is involved in the early establishment of left and right in the growing embryo.
The researchers then made full use of knowledge from previous studies of what PCSK6 and similar genes do in mice to reveal more about the biological processes involved.
Disrupting PCSK6 in mice causes ‘left-right asymmetry’ defects, such as abnormal positioning of organs in the body. They might have a heart and stomach on the right and their liver on the left, for example.
The researchers found that variants in other genes known to cause left-right defects when disrupted in mice were more likely to be associated with relative hand skill than you would expect by chance.
While the team has identified a role for genes involved in establishing left from right in embryo development, William Brandler cautioned that these results do not completely explain the variation in handedness seen among humans. He said: ‘As with all aspects of human behaviour, nature and nurture go hand-in-hand. The development of handedness derives from a mixture of genes, environment, and cultural pressure to conform to right-handedness.’
This work was supported by the University of St Andrews, the UK Medical Research Council, the Wellcome Trust, the Max Plank Society, and the EU 6th Framework Programme. University of Oxford

Although a family history of Alzheimer’s disease is a primary risk factor for the devastating neurological disorder, mutations in only three genes – the amyloid precursor protein and presenilins 1 and 2 – have been established as causative for inherited, early-onset Alzheimer’s, accounting for about half of such cases. Now Massachusetts General Hospital (MGH) researchers have discovered a type of mutation known as copy-number variants (CNVs) – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer’s. Notably, different genomic changes were identified in the Alzheimer’s patients in each family.
The study was conducted as part of the Alzheimer’s Genome Project – directed by Rudolph Tanzi, PhD, director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH) and a co-discoverer of the first three early-onset genes – and was supported by the Cure Alzheimer’s Fund and the National Institute of Mental Health (NIMH).
‘We found that the Alzheimer’s-afflicted members of these families had duplications or deletions in genes with important roles in brain function, while their unaffected siblings had unaltered copies of those genes,’ says Basavaraj Hooli, PhD, of the Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, lead author of a report that has been published online in Molecular Psychiatry. ‘Since our preliminary review of the affected genes has provided strong clues to a range of pathways associated with Alzheimer’s disease and other forms of dementia, we believe that further research into the functional effects of these CNVs will provide new insights into Alzheimer’s pathogenesis.’ Hooli is a research fellow in Neurology at Harvard Medical School.
Most studies searching for genes contributing to Alzheimer’s risk have looked for variants in a single nucleotide, and while thousands of such changes have been identified, each appears to have a very small impact on disease risk. Recently research has found that CNVs – in which DNA segments of varying lengths are deleted or duplicated – have a greater impact on genomic diversity than do single-nucleotide changes. This led Tanzi and his team to search for large CNVs in affected members of families with inherited Alzheimer’s disease. ‘These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995, when we co-discovered the presenilins. As with those original genes, we hope to use the information gained from studies of the new Alzheimer’s mutations to guide the development of novel therapies aimed at preventing and treating this devastating disease.’ Tanzi explains.
The investigators reviewed genomic data from two sources – the NIMH Alzheimer’s Disease Genetics Initiative and the National Cell Repository for Alzheimer’s Disease – and focused on 261 families with at least one member who developed Alzheimer’s before the age of 65. Using a novel algorithm they had developed for analyzing CNVs, the researchers identified deletions or duplications that appeared only in affected members of these families. Two of these families had CNVs that included the well-established amyloid precursor protein gene, but 10 others were found to have novel Alzheimer’s-associated CNVs, with different gene segments being affected in each family.
While none of the novel variants have previously been associated with Alzheimer’s disease, most of them affect genes believed to be essential to normal neuronal function, and several have been previously associated with other forms of dementia. For example, one of the identified CNVs involves deletion of a gene called CHMP2B, mutations of which can cause ALS. In another family, affected members had three copies of the gene MAPT, which encodes the tau protein found in the neurofibrillary tangles characteristic of Alzheimer’s. Mutations in MAPT also cause frontotemporal dementia.
Hooli explains, ‘Potential clinical application of the findings of this study are not yet clear and require two additional pieces of information: similar studies in larger groups of families with inherited Alzheimer’s to establish the prevalence of these CNVs and whether the presence of one ensures development of the disease, and a better understanding of how these variants affect neuronal pathways leading to the early-onset form of Alzheimer’s disease.’ Massachusetts General Hospital