NEW YORK – Through reanalysis of genetic data from tens of thousands of families affected by autosomal recessive developmental disorders (ARDD), a team led by investigators at the Wellcome Sanger Institute and GeneDx has demonstrated that at least 80 percent of cases could be explained by variants in genes previously implicated in such conditions.
"This study expands our understanding of the genetic architecture of developmental disorders across diverse, genetically inferred ancestry groups and suggests that improving strategies for interpreting missense variants in known ARDD genes may help diagnose more patients than discovering the remaining genes," co-senior and corresponding author Hilary Martin, a researcher at the Wellcome Sanger Institute, and her colleagues wrote in a paper published in Nature Genetics on Monday.
Building on findings from earlier studies, including one published in Science in 2018 that centered on ARDD contributors in protein-coding genes in families of European or South Asian ancestry, Martin and her colleagues looked at exome sequencing data from 13,450 affected individuals from the Deciphering Developmental Disorders study and 36,057 provided by genetic testing company GeneDx.
The participants included individuals from 22 genetically inferred ancestry groups from African, Latin American, East Asian, European, Middle Eastern, and South Asian populations, spanning 29,745 affected families.
In this diverse dataset, the team saw signs that recessive contributors to developmental disorders tended to notch up with increasing autozygosity in a population, as individuals inherit both copies of certain DNA sequences from a shared ancestor of related parents.
While the team did track down suspicious variants in new developmental disorder genes— particularly KBTBD2 and ZDHHC16 — the reanalysis suggested that around 84 percent of cases involved variants in genes with known ties to such conditions.
"Although there are clearly more recessive DD-associated genes to find, these are unlikely to account for many diagnoses," Martin said in an email, noting that the team's estimates suggested unknown genetic contributors explain around 1 percent of the ARDD cases in the current study.
In particular, the investigators found that more than 34 percent of ARDD cases were marked by variants in recognized development disorder genes that were not classified as pathogenic in the ClinVar database, pointing to diagnoses that may be missed due to interpretation gaps.
In addition, the investigators unearthed multiple genetic contributors in some 12.5 percent of the developmental disorder cases, pointing to complexity within the cohorts.
"Amongst patients who already have a genetic diagnosis, there is still an excess of new (de novo) damaging mutations above what we expect by chance, suggesting that some of these patients probably have an additional de novo variant contributing to their condition," Martin explained, adding that such variants often fell outside of known developmental disorder genes in patients known to have a "partial" diagnosis.
More broadly, the latest results highlight the importance of continuing to tease out protein-coding contributors in established ARDD genes with the help of carrier frequency data from healthy populations, coupled with experimental data.
Together, the results suggested that investigators should continue their gene discovery efforts, "focusing on de novo mutations, even among patients we think are diagnosed," Martin suggested, noting that the findings may also potentially help with recurrence risk counseling for parents with an ARDD-affected child.