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Genomics in the Journals: 2013.10.03

NEW YORK (GenomeWeb News) – In Nature Genetics, researchers from Baylor College of Medicine, the University of Texas, and elsewhere described point mutations that can truncate an imprinted gene called MAGEL2, causing autism spectrum disorder and features found in Prader-Willi syndrome.

The team unearthed the first of these MAGEL2 mutations by doing whole-genome sequencing on an individual with ASD, mild intellectual disability, and symptoms resembling Prader-Willi syndrome. An analysis of exome sequence data representing 1,248 more cases already assessed in a clinical lab led to three more individuals with ASD, Prader-Willi-like features and intellectual disability who carried similar changes to MAGEL2.

The gene falls in a chromosome 15 region where maternally inherited alleles are usually silenced and paternal alleles expressed, the study's authors noted. In individuals with Prader-Willi syndrome, paternal sequence expression from that part of the genome is generally lacking.

Consistent with previously described patterns in Prader-Willi syndrome, researchers found that all four individuals had mutations affecting the copy of MAGEL2 inherited from the father's side.

For another Nature Genetics paper, members of the International Multiple Sclerosis Genetics Consortium highlighted four-dozen new MS risk loci found through an immune-focused genome-wide association study.

The group used the custom ImmunoChip array to genotype almost 14,500 individuals with MS and 24,091 unaffected control individuals, unearthing 135 loci with potential ties to MS.

From there, researchers did replication testing of variants at these candidate sites and other loci described in past MS studies, using samples from tens of thousand more cases and controls.

Following that phase of the study — together with a joint analysis of data from the discovery and replication cohorts — they were left with significant MS associations at around 100 sites in the genome, including 48 loci not reported previously.

"[T]here are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex," study authors wrote, noting that their additional fine mapping analysis made it possible to further define a handful of these associations.

A Yale University-led team reporting in Science Translational Medicine presented a blood gene expression signature that seems to show promise for predicting outcomes for individuals affected by a lung condition called idiopathic pulmonary fibrosis.

Through array-based gene expression profiling on blood samples prospectively collected from 45 individuals with IPF, the group tracked down 52 genes showing expression patterns that appeared to differ depending on the individuals' transplant-free survival over time.

Researchers went on to verify that result during a replication stage of the study, which included samples from another 75 individuals. There, they found that the signature could classify patients into groups with significantly different odds of transplant-free survival. They also noted that expression of four of the genes — CD28, ICOS, LCK, and ITK — was dialed down in individuals with poor overall survival patterns.

"Given the fact that lung transplantation is the only therapy that has shown to improve survival in IPF, our test could allow physicians to refer IPF patients for lung transplant at the right time — not too late and not too early," senior author Naftali Kaminski, pulmonary, critical care, and sleep medicine chief at the Yale School of Medicine, said in a statement.

A New England Journal of Medicine study outlined findings from the first 250 cases assessed by whole-exome sequencing at Baylor College of Medicine's CLIA-certified clinical diagnostic labs.

With the help of sequencing, interpretation, and mutation verification pipelines designed to support the diagnostic sequencing program, the researchers did whole-exome sequencing on 250 individuals with undefined genetic conditions who were referred to the program by physicians starting in October, 2011.

In situations where those exome sequences yielded alleles that were expected to have clinical significance, the team used Sanger sequencing to validate the changes prior to providing information to physicians via focused and expanded reports.

In the initial 250 cases considered in the diagnostic exome sequencing program, the study's authors tracked 86 apparently causative mutations affecting 62 individuals. Those newly diagnosed cases included 33 individuals with autosomal dominant genetic conditions and 16 individuals who had autosomal recessive disease. Another nine individuals were diagnosed with X-linked conditions, while four appeared to have two different sorts of genetic conditions.

"[T]he use of whole-exome sequencing to analyze 250 consecutive clinical cases yielded a diagnosis in [25 percent] of these cases," they concluded, "which supports the use of whole-exome sequencing as a diagnostic test for patients with non-specific or unusual disease presentations of possible genetic cause and for patients with clinical diagnoses of heterogeneous genetic conditions."

"Questions about cost-effectiveness, accuracy, yield, and effective integration of genome-based diagnosis in medical care must be addressed in future studies and will require prospective study designs," the researchers added.