Skip to main content

Gene Developmental Disorder

Most new recessive developmental disorder diagnoses lie within known genes, say scientists


Scientists have conducted the largest and most diverse study to date on how recessive genetic changes contribute to developmental disorders. They found that most undiagnosed cases that are due to recessive causes are linked to genes we already know about, and suggest a shift in research focus could improve diagnosis rates.

Researchers from the Wellcome Sanger Institute and their 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 to previous work.

While discovering several genes that were previously not linked to these conditions, researchers found that known genes explain over 80% of cases caused by recessive genetic variants. This is a significant increase from previous estimates. The study also revealed the contribution of recessive genetic variants to developmental disorders varies significantly across the ethnic groups studied.

The findings, published 23 September in Nature Genetics, 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.

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 say.

Many developmental disorders, which can impact a child's physical, intellectual, or behavioral development, have genetic origins. 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. Until now, overall quantification of these recessive genetic causes across diverse populations has not been done.

In this new study, researchers combined summarized data from the Deciphering Developmental Disorders (DDD) study and GeneDx cohorts to identify individuals with similar genetic backgrounds, totaling 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.

The team found the number of patients affected by recessive genetic variants varied greatly between different ancestry groups, ranging from two to 19% of cases. This variation is strongly linked to the prevalence of unions between close relatives—consanguinity—in these groups.

Researchers identified several genes, including KBTBD2, CRELD1 and ZDHHC16, newly associated with developmental disorders, providing answers for previously undiagnosed families. They also estimate that around 12.5% of patients may have multiple genetic factors contributing to their condition, highlighting the complexity of these disorders.

Importantly, they found known genes explain about 84% of cases caused by recessive genetic variants, which was similar across individuals from European and non-European ancestry groups.

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 emphasize the importance of improving interpretation of harmful genetic variants in known disease-causing genes.

Dr. Kartik Chundru, first author of the study, formerly at the Wellcome Sanger Institute and now 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."

Dr. Vincent Ustach, senior author of the study at GeneDx, said, "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 personalized and actionable results for families with affected children, and overall enhances our ability to provide answers for underrepresented populations."

Dr. Hilary Martin, senior author of the study at the Wellcome Sanger Institute, said, "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."

#RecessiveDisorders, #GeneticResearch, #KnownGenes, #Mutations, #Diagnosis, #Treatment, #WholeExomeSequencing, #GeneticCounseling, #CausativeVariants, #TherapeuticStrategies, #GeneticLinks, #EnvironmentalFactors, #DevelopmentalDelays, #HereditaryConditions, #PersonalizedMedicine, #PhenotypeGenotypeCorrelation, #GeneIdentification, #MedicalGenetics, #Research, #Genomics

International Conference on Genetics and Genomics of Diseases 

Comments

Popular posts from this blog

Fruitful innovation

Fruitful innovation: Transforming watermelon genetics with advanced base editors The development of new adenine base editors (ABE) and adenine-to-thymine/ guanine base editors (AKBE) is transforming watermelon genetic engineering. These innovative tools enable precise A:T-to-G and A:T-to-T base substitutions, allowing for targeted genetic modifications. The research highlights the efficiency of these editors in generating specific mutations, such as a flowerless phenotype in ClFT (Y84H) mutant plants. This advancement not only enhances the understanding of gene function but also significantly improves molecular breeding, paving the way for more efficient watermelon crop improvement. Traditional breeding methods for watermelon often face challenges in achieving desired genetic traits efficiently and accurately. While CRISPR/Cas9 has provided a powerful tool for genome editing, its precision and scope are sometimes limited. These limitations highlight the need for more advanced gene-e...

Genetic factors with clinical trial stoppage

Genetic factors associated with reasons for clinical trial stoppage Many drug discovery projects are started but few progress fully through clinical trials to approval. Previous work has shown that human genetics support for the therapeutic hypothesis increases the chance of trial progression. Here, we applied natural language processing to classify the free-text reasons for 28,561 clinical trials that stopped before their endpoints were met. We then evaluated these classes in light of the underlying evidence for the therapeutic hypothesis and target properties. We found that trials are more likely to stop because of a lack of efficacy in the absence of strong genetic evidence from human populations or genetically modified animal models. Furthermore, certain trials are more likely to stop for safety reasons if the drug target gene is highly constrained in human populations and if the gene is broadly expressed across tissues. These results support the growing use of human genetics to ...

Genetics study on COVID-19

Large genetic study on severe COVID-19 Bonn researchers confirm three other genes for increased risk in addition to the known TLR7 gene Whether or not a person becomes seriously ill with COVID-19 depends, among other things, on genetic factors. With this in mind, researchers from the University Hospital Bonn (UKB) and the University of Bonn, in cooperation with other research teams from Germany, the Netherlands, Spain and Italy, investigated a particularly large group of affected individuals. They confirmed the central and already known role of the TLR7 gene in severe courses of the disease in men, but were also able to find evidence for a contribution of the gene in women. In addition, they were able to show that genetic changes in three other genes of the innate immune system contribute to severe COVID-19. The results have now been published in the journal " Human Genetics and Genomics Advances ". Even though the number of severe cases following infection with the SARS-CoV-...