Researchers have conducted what they say is the largest and most diverse study to date on how recessive genetic changes contribute to developmental disorders. The team, headed by researchers at the Wellcome Sanger Institute, together with collaborators at GeneDx, analyzed genetic data from nearly 30,000 families affected by developmental disorders— six times more families with greater diversity in ancestral backgrounds, compared with previous work.
Their results indicated that most undiagnosed cases that are due to recessive causes are linked to recognized autosomal recessive developmental disorder-associated (ARDD) genes, and the scientists suggest a shift in research focus could improve diagnosis rates. They say the findings shed new light on the genetic basis of developmental disorders and highlight the importance of considering a person’s genetic background in diagnosis and research.
Kartik Chundru, PhD, formerly at the Wellcome Sanger Institute and now at the University of Exeter, said, “These gene discoveries will provide answers for some previously undiagnosed families and help clinicians better understand and identify these conditions. Our study highlights the importance of reanalyzing genetic data with updated methods and knowledge, as it can lead to new diagnoses for patients without needing additional samples.”
Chundru is first author of the team’s published paper in Nature Genetics, titled “Federated analysis of autosomal recessive coding variants in 29,745 developmental disorder patients from diverse populations.”
Many developmental disorders, which can impact a child’s physical, intellectual, or behavioural development, have genetic origins. “High-throughput exome and genome sequencing have revolutionized the diagnosis of developmental disorders, typically allowing 30–40% of patients to obtain a genetic diagnosis,” the authors wrote. Some are caused by recessive genes, where a child must inherit an altered gene copy from both parents to develop the condition. They include Joubert syndrome, Bardet-Biedl syndrome and Tay-Sachs disease. “Autosomal recessive coding variants are well-known causes of rare disorders,” the authors continued, and while “The genetic architecture of developmental disorders has been shown to vary between genetically defined ancestry groups …” overall quantification of these recessive genetic causes across diverse populations has not been done.
For their newly reported study Chundru and colleagues combined summarised data from the Deciphering Developmental Disorders (DDD) study and GeneDx cohorts to identify individuals with similar genetic backgrounds, totalling 29,745 families. Over 20% of these families were from mostly non-European ancestries. Analyzing this large dataset provided more insight, especially for smaller and less-studied groups.
While discovering several genes that were previously not linked to these conditions, the researchers found known genes explain more than 80% of cases caused by recessive genetic variants, which was similar across individuals from European and non-European ancestry groups. “We found that the majority of the autosomal recessive burden is explained by known ARDD genes and that this is true both for European-ancestry and non-European-ancestry individuals (87% versus 80%),” they wrote.
This substantial increase from previous estimates suggests that the new recessive genes that have been discovered over the last few years account for a substantial fraction of previously undiagnosed patients with recessive causes. However, the scientists found that there are likely still diagnoses being missed in these known genes that involve DNA changes that are difficult to interpret. The findings emphasise the importance of improving interpretation of harmful genetic variants in known disease-causing genes.
The team suggests that efforts to discover recessive genes associated with these disorders in the last few years have been largely successful and that the challenge now lies more in interpreting genetic changes in known recessive genes. Using this approach could potentially be used to diagnose twice as many patients compared to focusing solely on remaining gene discovery, they suggest.
The study in addition found that the number of patients affected by recessive genetic variants varied greatly between different ancestry groups. “The estimated fraction of patients attributable to exome-wide autosomal recessive coding variants ranged from ~2–19%,” the authors stated. This variation is strongly linked to the prevalence of unions between close relatives—consanguinity—in these groups.
The researchers did identify several genes that were newly associated with developmental disorders, providing answers for previously undiagnosed families. “Overall we believe there is strong evidence that CRELD1, KBTBD2, ZDHHC16 and HECTD4 are bona fide ARDD genes,” they wrote. The investigators also estimated that around 12.5% of patients may have multiple genetic factors contributing to their condition, highlighting the complexity of these disorders. “…our burden analyses conducted in patients who already have a single genetic diagnosis imply that in as many as ~12.5% of these patients (~743), an as-yet-unidentified de novo mutation in another gene also contributes to the phenotype; almost all of this burden is outside known monoallelic and X-linked dominant DDG2P genes,” the scientists pointed out. They suggest that if these contributing de novo mutations could be identified it would “more than double the number of patients in these cohorts who currently have a composite genetic diagnosis.”
Hilary Martin, PhD, co-senior author of the study at the Wellcome Sanger Institute, pointed out, “One of the surprising findings from this work was that many patients with one known genetic diagnosis might actually have additional rare genetic changes contributing to their condition. Identifying these additional changes could improve our understanding of the patient’s condition, lead to more accurate diagnoses, and potentially offer new treatment options. It also highlights the complexity of genetic disorders and the need for comprehensive genetic analysis.”
Co-senior study author, Vincent Ustach, PhD, at GeneDx, added, “This is the most diverse group of participants ever studied to address the recessive contribution to developmental disorders, and showcases the critical impact that a diverse dataset has for delivering a more comprehensive understanding of developmental disorders across different ancestries. Findings from this study can drive more personalised and actionable results for families with affected children, and overall enhances our ability to provide answers for underrepresented populations.”
The study data can be accessed at https://github.com/chundruv/DDD_GeneDx_Recessives
