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Rare Disease Gene Detected Using Exome Sequencing, Disease Network Approach

By a GenomeWeb staff reporter

NEW YORK (GenomeWeb News) – Through an exome sequencing, homozygosity mapping, and disease network analyses-based study that involved individuals from a single Palestinian family, researchers from the US and Israel have identified a new genetic culprit behind a rare condition called hereditary spastic paraparesis.

Past studies have implicated dozens of genetic loci and about 20 genes in HSP, a set of progressive neuropathological conditions that are inherited in a Mendelian manner when disease-related mutations occur in any one of these genes. Now, researchers have added another HSP gene to the list: the kinesin gene KIF1A. The work is set to appear in an early, online paper in Genome Research this week.

"[W]ith the current methodology, we were able to rule out other genes and nail down this mutation in a single family," corresponding author Yaniv Erlich, a researcher at the Whitehead Institute for Biomedical Research, said in a statement. "Our next goal is to be able to find the causative mutation with a single affected person, fully moving into the era of personal genomics."

HSP conditions are characterized by progressive axonal degradation that eventually leads to muscle weakness and spasticity affecting lower limb function, including the way individuals walk, researchers explained. Past work has shown that the Mendelian disease can be passed down in an autosomal dominant, autosomal recessive, or X-linked manner.

For the current study, the team focused on one Palestinian family in which three of seven children — brothers between the ages of 14 and 20 years old — had HSP.

Using an Agilent 1-million feature hybrid capture array combined with Illumina paired-end sequencing, the team first sequenced the exomes of one of the affected children, a 15-year-old boy with HSP, and both of the unaffected parents.

They also genotyped the two other affected children using the Affymetrix GeneChip Human Mapping 250K Nsp array.

Researchers came up empty-handed when they sifted through the data looking for alterations affecting known HSP genes, leading them to believe that the HSP cases in the family stemmed from mutations in a yet unknown HSP gene.

Because the mother and father came from the same village, the team suspected that they may have been related to one another, upping the chances that a disease-related mutation would fall in homozygous sequence runs.

To look for such mutations, the team used homozygosity mapping in tandem with disease-network analyses assessing features such as gene expression, pathway information, and more.

"Accumulating lines of evidence have shown that genes that are associated with phenotypically close disorders are prone to have similar molecular signatures," they explained. "These include similar expression profiles, participation in the same signaling or metabolic pathways, or sharing similar protein domains."

From the 44 genes initially detected in four homozygous runs shared between HSP-affected brothers, the researchers homed in on 15 candidate genes containing five variant sites.

By doing disease network analyses of these genes with a trio of algorithms, they found a single gene that seemed to be linked to HSP in the family: the kinesin gene KIF1A.

Indeed, their subsequent Sanger sequencing studies verified that all three affected children carried homozygous mutations in the gene, while their unaffected parents and siblings were heterozygous for the mutation.

The results are consistent with past research linking kinesin function to diseases that involve axon problems, the authors explained, validating their combined disease network strategy for paring down suspicious genes identified by other methods.

"Disease-network analysis adds a complementary layer of information to the sequencing data," they wrote. "It provides a means to integrate prior knowledge on the expected molecular signature of the disease from closely associated conditions and to reject bystander variations."

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