NEW YORK (GenomeWeb) – Clinical genomics can offer increased diagnostic yield for intellectual disability, according to a team led by researchers at the King Faisal Specialist Hospital and Research Center.
In parallel with standard clinical tools, the team prospectively used genomic tools to suggest diagnoses for more than 300 people with intellectual disability. As King Faisal's Fowzan Alkuraya and his colleagues reported in Molecular Psychiatry this week, the genomic approach offered a likely diagnosis in nearly 60 percent of cases, while standard tools suggested one in only 16 percent of cases. At the same time, the genomic approach uncovered novel disease variants and confirmed previously reported ones.
"Genomic testing of individuals with ID offers a higher diagnostic yield than the standard workup," Alkuraya and his colleagues wrote in their paper. "The data we present in this study suggest that genomic sequencing should be considered early on in the diagnostic workup of these individuals in parallel with or after a negative result of molecular karyotyping."
The researchers began with a cohort of 337 children with intellectual disability, and divided them based on whether their case was familial or simplex. They noted that previous studies examining diagnostic yield of genome sequencing testing relied on pre-selected individuals for whom standard approaches had been unable to find a causal mutation. Here, they used genomic testing as first-tier test, though they simultaneously ran standard tests for comparison.
Familial cases underwent gene panel and fragile X testing. If that failed to uncover a diagnosis, the cases then underwent whole-exome sequencing. Similarly, simplex cases underwent molecular karyotyping and fragile X testing, and if that didn't uncover a diagnosis, they then went through gene panel testing. If that still didn't lead to a diagnosis, the cases underwent whole-exome sequencing. A portion of the cohort, some 129 cases went straight to whole-exome sequencing.
This genomic approach was able to reveal a likely diagnosis in 58 percent of cases, Alkuraya and his colleagues reported. Molecular karyotyping, multi-gene panel testing, and whole-exome sequencing uncovered pathogenic or likely pathogenic CNVs or SNVs in 27 percent, 34 percent, and 39 percent of tested cases, respectively.
In the 129 cases that went straight to whole-exome sequencing — the patients were recruited before the multi-gene panel was available — there was a diagnostic yield of about 60 percent, they added.
By comparison, standard clinical evaluation led to a likely diagnosis in 16 percent of cases, of which 70 percent were later confirmed, the researchers noted.
Of the pathogenic or likely pathogenic variants uncovered this cohort, the researchers reported finding eight novel CNVs, 46 known CNVs, 68 novel SNVs, and 77 known SNVs. Most of the causal SNVs identified were recessive and private, and not found in a set of 1,500 ethnically matched exomes. But some genes were implicated in more than one family — for instance, truncating mutations in NEMF and DNHD1 were found in two families each.
While some variants were in genes already linked to disease, others were located in genes like SYDE2, which is involved in axonal guidance in C. elegans, or KLHL24, which is expressed in the rat brain.
But even genes that aren't linked to the natural history of the disease could affect its clinical management, Alkuraya and his colleagues noted. They reported uncovering a truncating mutation in the SLC39A14 gene in a girl with unexplained neurodegenerative disease. This gene encodes ZIP14, which transports trace elements. When they examined levels of trace elements in the girl's blood, they uncovered high manganese levels, leading them to start chelation therapy. She is currently being monitored, the researchers added.
The authors further noted that their results "support the adoption of genomics as a first-tier test for individuals with ID."