NEW YORK – The United Arab Emirates last month launched a mandatory national premarital genetic screening program, in which all Emiratis seeking to wed will be required to be screened for over 840 autosomal recessive diseases.
The program is the latest of several public health initiatives either underway or soon to be launched that derive from the Emirati Genome Program (EGP), a national effort to establish a reference genome to help guide personalized and preventive healthcare throughout the UAE, elucidate patterns of rare genetic disorders in the Emirati population, and develop new treatments.
Alongside the premarital screening program, the UAE is using EGP data to enable pharmacogenetics reports for all its citizens and screen Emirati women for breast and ovarian cancer, and will soon offer HLA typing to improve organ and stem cell transplant and blood transfusion success rates.
The Abu Dhabi Department of Health (DoH), health technology company M42, and Khalifa University have been conducting validation and benchmarking studies of the short- and long-read sequencing platforms used in the EGP and its related clinical application programs, and presented the results of those studies in a series of posters at the American Society of Human Genetics annual meeting earlier this month in Denver.
For all the EGP-related programs, M42 and its collaborators at Abu Dhabi DoH and Khalifa University have been comparing short- and long-read sequencing platforms. The short-read platforms are Illumina's NovaSeq 6000 and MGI's DNBSeq-T10, while Oxford Nanopore Technology's (ONT) Promethion 48 is used for long-read sequencing.
The combination of these sequencing technologies aims to deliver a comprehensive view of the human genome. The Illumina and MGI platforms offer the high resolution and high accuracy of short-read sequences, enabling the identification of known and novel variants uniquely associated with the Emirati population, while ONT's platform can access regions that are usually more difficult to reach via short-read sequencing and view larger structural changes in the genome.
"Long reads provide more understanding of genomic structural variation, which is not as well understood with short reads," said Tiago Magalhães, VP of informatics at M42, adding that long reads are also capable of providing methylation information.
As described in the ASHG posters, an initial analysis of 160,000 whole genomes in the EGP database (of about 600,000 sequenced genomes in total so far) found that all three platforms had similarly high pass rates and performed similarly with respect to single nucleotide polymorphisms (SNPs), while the Illumina and MGI sequencers returned fewer false positives than ONT in terms of indels.
All three platforms also performed similarly in predicting responses to a panel of 126 drugs. The UAE has implemented a national pharmacogenomics program based on EGP data, wherein any physician may order a patient's PGx report via an online portal called Malafi, which was made through collaboration between DoH and M42.
Finally, the three sequencing platforms also showed comparable performance in HLA typing. M42 is currently working to present the Abu Dhabi DoH with a plan for a national HLA registry.
Fowzan Alkuraya, chief medical and genomics officer at Lifera Omics, said that he sees "added value" in incorporating long-read sequencing into public health initiatives.
"Haplotype phasing is much more straightforward using long-read sequencing and this is particularly relevant for populations where haplotype information is limited such as the Middle East," he said. "Additionally, many clinically relevant genes are very challenging to sequence using short-read sequencing and this becomes a major limitation for population-level screening programs such as expanded carrier screening. Long-read sequencing offers a single test solution to [expanded carrier screening] instead of having supplemental tests when short-read sequencing is used in these efforts."
ONT has recently been making inroads in the Middle East. Last month, for example, Saudi Arabia's King Abdullah University of Science and Technology developed a rapid and low-cost nanopore sequencing assay for pinpointing complex breakpoints in genomic disorders at base resolution.
Premarital carrier screening
The premarital screening program is an initiative aimed at reducing the burden of inherited disorders on the UAE healthcare system. The UAE, as well as most other Middle Eastern nations, experiences a higher rate of autosomal recessive disorders due to a relatively high rate of consanguinity. Some studies estimate that 50 percent or more of Emiratis, Qataris, and Kuwaitis marry close relatives.
Many other Middle Eastern states offer their own premarital carrier screening programs as a means of alleviating the burden of inherited disorders on their respective national healthcare systems, although not all are obligatory. Mandatory screening programs have so far been implemented in Jordan, Bahrain, Saudi Arabia, Turkey, and now the UAE.
Mohamed Alameri, section head for studies and special projects in the Abu Dhabi DoH, said that the goal of the program is simply to provide couples with better family planning tools and that although Emiratis will not be allowed to marry without screening, no marriage will be prevented on account of test results. Additionally, he said, all couples will have lifetime access to in vitro fertilization, paid for by the Emirati government.
"Whatever they decide on, they will be insured throughout their lives," Alameri said. "We're holding their hands until they have a healthy baby. That's the goal."
The carrier assay covers 572 genes implicated in over 840 autosomal recessive diseases. Testing is done through Pure Health, the largest integrated healthcare network in the UAE, which operates approximately 14 hospitals and 46 clinics.
In a study conducted with health technology company M42 and Khalifa University, the Abu Dhabi DoH analyzed carrier screening data from 1,118 couples and found that approximately 11 percent of those couples carry at least one pathogenic variant.
With an estimated 10,000 marriages per year in Abu Dhabi, Alameri said that around 400 couples might potentially benefit from this screening per month.
Studies have shown that premarital screening efforts have had mixed success in driving down the rates of some inherited diseases. According to a 2015 review article in Public Health Genomics, Turkey's program, instituted in the 1990s, resulted in the cancellation of 53 percent of at-risk marriages and an 80 percent reduction in at-risk births, while Bahrain similarly saw an approximately 43 percent cancellation rate of at-risk marriages. Saudi Arabia experienced a drop in the prevalence of β-thalassaemia from approximately 33 percent to 9 percent following the implementation of its mandatory premarital screening program, although the study notes that here, "the program's objective of decreasing high-risk marriages was not as successful.".
Still, the mandatory nature of these programs remains controversial. Jnetics, a charity dedicated to improving the prevention and diagnosis of Jewish genetic disorders in the UK, drew a parallel between the UAE's program and efforts to conduct widespread Tay-Sachs Disease screening throughout the Jewish community, while raising especial concern over how the government may use its citizens' data when one cannot decline to share that data.
In a recent blog post on the UAE program, Jnetics wrote that concerns over how personal genetic information is used "depends how much you trust the government," noting that this will vary from one culture to another.
In fact, some studies have found relatively high rates of acceptance of mandatory premarital carrier screening programs across the Middle East. For example, a 2021 study from Jordan published in Public Health Genomics found that nearly 88 percent of 432 participants surveyed held a positive attitude towards Jordan's program.
"All this pharmacogenomics, the premarital screening, oncology [screening], is all part of this idea that [with] the EGP, you sequence once, but then you analyze for life," Magalhães said.