NEW YORK – New research from Australia suggests that couples-based screening across a large set of genes is a feasible way of identifying potential carriers of autosomal recessive or X-linked genetic disease variants in a diverse, general population. Testing provided insights that many of the participating couples may use when making reproductive decisions.
In a paper published in the New England Journal of Medicine on Wednesday, investigators at the Murdoch Children's Research Institute and elsewhere presented findings from a genomic sequencing-based carrier screening study known as the Mackenzie's Mission project, which enrolled 10,038 couples from across Australia. The Australian government-funded study was conducted through the Genomics Health Futures Mission, with an eye toward offering carrier screening to diverse individuals from the general population in Australia.
"This is the first nationwide study, to our knowledge, that has examined couple screening for a very large number of genes in a country that is geographically very large with some individuals living thousands of kilometers from a major city," co-first and corresponding author Martin Delatycki, codirector of the Murdoch Children's Research Institute and clinical geneticist at Victorian Clinical Genetics Services, said in an email.
The effort "was designed to examine the feasibility of offering screening in this way," he explained, "and examining outcomes in terms of uptake, frequency of high chance couples, decisions made by those couples, satisfaction with the program, and psychosocial outcomes."
Based on targeted panel sequencing of almost 1,300 genes in 9,107 couples who completed the screening process, the team unearthed pathogenic variants in 90 genes and found 175 couples to be at high risk of having a child affected by at least one of the genetic autosomal recessive or X-linked conditions considered.
In contrast, when the researchers sequenced more than 1,000 disease-related genes in individuals rather than couples, they found that almost 93 percent of them were carriers of disease variants.
"We demonstrated that couples-based screening is feasible and acceptable, streamlines the carrier screening process, and reduces the laboratory and genetic counselor resources required," Delatycki said.
Nearly three-quarters of the conditions identified in the couples-based carrier screening analysis were autosomal recessive, and 80 percent were not among the conditions that are tested through government-funded programs in Australia at the moment, such as cystic fibrosis.
The majority of couples felt positive about their decision to participate in the screening study, the team reported, and almost 80 percent of the couples who learned of their genetic carrier risk had or planned to take steps in reproduction such as in vitro fertilization paired with preimplantation genetic testing.
Nearly 35 percent of participants reported low and almost 41 percent moderate anxiety, though anxiety notched up in a subset of participants from couples with genetic disease-related variants.
Though the investigators noted that cultural, linguistic, and ethnic considerations should be taken into account if such a program is expanded, their results so far suggested a couples-based carrier screening strategy "was largely acceptable to participants and was used to inform reproductive decision making."
"The study demonstrated that screening can be done in a diverse population," Delatycki said, adding that "[i]f a government elects to fund screening so that all individuals have equitable access to it, the process developed by the study can be expanded to enable this to take place."
The team is continuing to follow couples who were identified as carriers in the screen to find out more about the reproductive decisions they make in the longer term, he explained. Members of the group are also working with a Health and Aged Care department of Australia's federal government to come up with a carrier screening program that is "feasible, sustainable, and equitably delivered."
"Although the dataset for reproductive outcomes will take several years to collect, analysis of the current dataset indicates that couples with an increased chance of having a child with a relatively moderate or treatable condition were less likely to take measures to avoid the condition than couples with an increased chance of having a child with a severe condition," the authors noted. "This finding emphasizes the importance of focusing screening on genes associated with severe conditions."
In an editorial accompanying the study, Amsterdam University Medical Center human genetics researcher Lidewij Henneman, who was not involved in the research, said the work "provides lessons on how to implement carrier screening in practice."
"Because each population may have its own variant profile, providers in different countries may want to develop their own panels of genes associated with conditions occurring in the population," Henneman added. "On a global level, however, we can at least try to define and meet uniform criteria that delineate the scope and establish the key requirements for responsible implementation of carrier screening."