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Exome Study of Consanguineous Families With New Dysmorphology Syndromes Yields Plausible Dx for Most

NEW YORK (GenomeWeb) – Analyzing the genomes of consanguineous families with apparently novel dysmorphology syndromes, researchers from Saudi Arabia have found a plausible molecular diagnosis for 90 percent, mostly in novel candidate genes.

Reporting detailed clinical and genomic analyses likes these through exchange databases, they said, will likely help researchers and doctors discover and confirm novel disease syndromes more quickly.    

The team, led by Fowzan Alkuraya and colleagues at King Faisal Specialist Hospital and Research Center in Riyadh, reported their results online in Genetics in Medicine last week.

For their study, they took a close look at 31 consanguineous families with several affected members with a dysmorphology syndrome. Each family had a unique set of dysmorphic features and other symptoms that did not match a previously described syndrome.

Using microarray-based genotyping, the researchers first determined all autozygous intervals in the patients, meaning regions of homozygosity that stem from a common ancestor and resulted from consanguineous mating.

They then performed exome or whole-genome sequencing and identified candidate genes by focusing on variants that were located in the autozygome, had a low population frequency, and were predicted to affect the protein product of the gene.

Overall, they identified strong candidate variants in 28, or about 90 percent, of families. In the other three families, they found more than one possible causal variant, so they classified them as unsolved.

In 21 families, the candidate variant was located in a gene that had not been associated with a disease before, at least not at the time of the analysis, and the researchers presented 10 of these candidate genes for the first time in their paper.

In the remaining six families, the researchers found candidate mutations in known disease genes, even though their phenotype had seemed novel. For some families, they said, this was the case because previous publications of the disease gene only had a very limited description of the phenotype. For others, the phenotype was so different from the one described in the literature for that gene that it was impossible to match them.

"The relatively easy access to genomic sequencing tools has empowered many clinical geneticists to identify interesting novel candidate genes in their patients," the authors wrote, but many of these findings remain unpublished until confirmed by a second case with a matching phenotype and genotype.

However, reporting patients with novel candidate genes early, using tools such as GeneMatcher and MIMmatcher, will likely speed up the process of finding other cases and confirming the underlying genetic defect. "It is only through high-throughput identification and confirmation of disease-gene links that we can reap the benefits of full medical annotation of the human genome," they wrote.