NEW YORK (GenomeWeb) – Through a first-tier clinical exome sequencing program, researchers in Saudi Arabia identified 155 recessive genes that appear to be disease causing.
Researchers led by Fowzan Alkuraya from King Faisal Specialist Hospital and Research Center launched a clinical exome sequencing program in Saudi Arabia that took a "genomics-first" approach in which any clinician who suspected a patient had a genetic disorder could order testing. That testing was centralized and the cost covered by the Ministry of Health, enabling exome sequencing to be a first-tier genetic test.
"[T]his presented an unprecedented opportunity to create the most comprehensive view to date of clinically relevant variants across the entire spectrum of genetic diseases in a highly consanguineous population," Alkuraya and his colleagues wrote in their paper, noting that Saudi Arabia has a consanguinity rate greater than 50 percent.
They conducted clinical exome sequencing on more than 2,200 Saudi families and found the likely source of disease in about 43 percent of cases, as the researchers reported today in the American Journal of Human Genetics.
In particular, the researchers performed 3,310 clinical exome sequencing tests on 2,219 families, 1,653 of which involved index case sequencing only, though others involved the sequencing of family members, as well. Using ACMG variant guidelines, they classified these cases as "solved" if they uncovered a pathogenic or likely pathogenic variant that explained the condition affecting the family, as "ambiguous" if they uncovered a monoalleleic pathogenic or likely pathogenic variant or a variant of unknown significance in a disease gene, or as "negative."
Of these 2,219 cases, the researchers solved 961 cases, for a diagnostic yield of 43.3 percent. Most solved cases were due to autosomal recessive variants, though a portion were due to dominant variants.
In all, the researchers proposed 236 genes as candidate disease genes in this cohort, including 155 recessive, 74 dominant, and seven X-linked genes. For about a dozen of these genes, the researchers assigned a high level of confidence to their determination. This high confidence was usually due to independent mutations in the same gene being uncovered in different families with similar phenotypes. For instance, they noted two families with non-syndromic intellectual disability, each of which had a homozygous truncating variant in ALKBH8.
Other genes had lower levels of confidence. These included genes where knockout mice had a phenotype similar to the one seen in people or genes where there was some supporting biological connection, such as genes known to be involved in cilia biology being linked to ciliopathic disorder.
They further provided supporting evidence for 64 genes that had previously been identified as candidate genes.
Through their analysis, the researchers also uncovered recessive forms of genes previously only linked to dominant disorders. They found, for example, that a recessive variant in SLC4A10 was linked to the same intellectual disability and epilepsy phenotype as the dominant version, while the recessive form of POU4F3 was linked to an earlier onset of hearing loss than the dominant version.
Other times, they noted phenotypes that differed from those reported in the literature. They reported finding a truncating variant in TCF12 in an individual who did not have craniosynostosis, but did have the developmental delay that's linked to TCF12-related craniosynostosis 3.
In all, the researchers noted that clinical exome sequencing studies like this improve the understanding of variation within the human genomes and its clinical ramifications.
They also noted that this "genomics-first" approach could be advantageous: Of those individuals whose cases they were able to solve, nearly 78 percent did not have the correct diagnosis at the time when sequencing was requested.