Analysis of genetic variation in the exome, the DNA sequence of genes that are translated into protein, can aid in uncovering the cause of conditions for which no genetic cause could previously be found, and this can directly impact clinical management, the annual conference of the European Society of Human Genetics will hear today.
Dr Jayne Hehir-Kwa, Assistant Professor of Bioinformatics in the Translational Research group, Department of Human Genetics, Radboud UMC, Nijmegen, The Netherlands, will describe results from her group's study that set out to determine whether copy number variants (CNVs), large genomic deletions or duplications, can contribute to diseases other than intellectual disability.
The role of CNVs in intellectual disability is well known, but their implication in other conditions is less so. "There are, for example, case reports describing deletions in blindness, but no-one has determined the full extent of CNVs in other patient groups," Dr Hehir-Kwa will say.
The team screened 600 patients for which no diagnosis or causal mutation could be found using current whole exome sequencing (WES) methodology, and looked genome-wide for a causal deletion or duplication. It is, they say, the first time anyone has screened systematically for a disease mechanism in such a large and diverse patient group, including five heterogeneous conditions – intellectual disability, deafness, blindness, metabolic disorders, and movement disorders.
"For these patient groups, targeted gene approaches have been traditionally used for mutation screening and hence the contribution of CNVs to these disease groups has never been established and genome-wide testing rarely applied," says Dr Hehir-Kwa. "Our results show that CNVs are a relatively common, clinically-relevant event."
CNVs were found in patients with many different kinds of disorders, for example retinitis pigmentosa (blindness), Usher syndrome (deafness), Bethlem/Ulrich myopathy (a congenital form of muscular dystrophy), hypotonia-cystinuria syndrome (a neonatal-onset metabolic disorder) and X-linked immunodeficiency (an inherited disorder of the immune system).
"Although WES is not perfect in terms of completely cataloguing genomic variation, our work has shown that it can play an important part in diagnosis. In addition to helping us devise better clinical management strategies for patients, it also affects their prognosis and provides information which can aid us with reproductive counselling for affected individuals," says Dr Hehir-Kwa. "As a result, we are now offering the CNV screening performed in our study as a standard diagnostic procedure in exome analysis for patients where the genetic cause of their condition has not been found previously."
The diagnostic yield differs between the different disease categories, the researchers say. Traditional screening for genetic mutations can explain 27% of intellectual disability, 52% of blindness, and up to 20% of individuals with mitochondrial and movement disorders. "This means that between 48-80% of patients screened with WES are not given a genetic diagnosis. By looking for CNVs in the exon regions of these undiagnosed patients we estimate that we can find such a diagnosis in about a further four percent.
In particular, the blindness conditions seem to have the highest yield of CNVs – up to seven percent," says Dr Hehir-Kwa. "I would like to see screening for more types of genomic variants become standard procedure in genetic diagnostics. The genome of an individual can contain all kinds of different variants, in all shapes and sizes, and it is important that we take all these variations into account." WES, when offered as a first tier diagnostic test, can give a high diagnostic yield, and the result is faster diagnostics at lower cost.
"The more complete and thorough we can make such a diagnostic test, the more accessible we make genetic testing for the public. However, clinical health care professionals need to be well informed about the different genetic disease mechanisms to provide the best possible counselling for patients," Dr Hehir-Kwa will conclude.
Mary Rice | Eurek Alert!
Tissue-engineered colon from human cells develop different types of neurons
02.10.2015 | Children's Hospital Los Angeles
Big eyes! – MDC Researchers Identify Cause of Inherited Form of Extreme Nearsightedness
02.10.2015 | Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft
The Laser Zentrum Hannover e.V. (LZH) will present how laser-based technologies can contribute to the laboratory of the future at the LABVOLUTION in Hannover in Hall 9, Stand E67/09, from October 6th to 8th, 2015. As a part of the model lab smartLAB, the LZH is showing how additive manufacturing, better known as 3-D printing, can make experimental setups more flexible.
Twelve partners from science and industry are presenting an intelligent and innovative model lab at the special display smartLAB. A part of this intelligent...
Before embarking on a transcontinental journey, jet airplanes fill up with tens of thousands of gallons of fuel. In the event of a crash, such large quantities of fuel increase the severity of an explosion upon impact.
Researchers at Caltech and JPL have discovered a polymeric fuel additive that can reduce the intensity of postimpact explosions that occur during accidents and...
When surgical residents need to practice a complicated procedure to fashion a new ear for children without one, they typically get a bar of soap, carrot or an apple.
To treat children with a missing or under-developed ear, experienced surgeons harvest pieces of rib cartilage from the child and carve them into the framework...
Walking an obstacle course on Earth is relatively easy. Walking an obstacle course on Earth after being in space for six months is not quite as simple. The...
01.10.2015 | Event News
30.09.2015 | Event News
17.09.2015 | Event News
02.10.2015 | Medical Engineering
02.10.2015 | Materials Sciences
02.10.2015 | Trade Fair News