Most new diagnoses of recessive developmental disorders are in known genes, scientists say

Scientists have conducted the largest and most diverse study to date of how recessive genetic changes contribute to developmental disorders. They found that most undiagnosed cases due to recessive causes are linked to genes we already know about, and suggest that a change in the focus of research 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, a six-fold increase in families with greater diversity of ancestral origins compared to previous work.

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

The results, published on September 23 in Genetics of natureshed new light on the genetic basis of developmental disorders and highlight the importance of taking a person’s genetic heritage into account in diagnosis and research.

The team suggests that efforts in recent years to discover recessive genes associated with these disorders have been largely successful, and that the challenge now is to interpret genetic changes in known recessive genes. This approach could potentially be used to diagnose twice as many patients as if one focused only on discovering the remaining genes, 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 copy of the gene from both parents to develop the condition. These include Joubert syndrome, Bardet-Biedl syndrome, and Tay-Sachs disease. To date, comprehensive quantification of these recessive genetic causes in diverse populations has not been done.

In this new study, researchers combined summary data from the Deciphering Developmental Disorders (DDD) study and GeneDx cohorts to identify individuals with similar genetic backgrounds, a total of 29,745 families. More than 20% of these families were mostly of non-European ancestry. Analyzing this large dataset provided more precise information, particularly for smaller, less-studied groups.

The team found that the number of patients affected by recessive genetic variants varied considerably across ancestry groups, ranging from 2 to 19 percent of cases. This variation is closely related to the prevalence of close-kin unions – consanguinity – in these groups.

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

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

This substantial increase over previous estimates suggests that the new recessive genes that have been discovered in recent years account for a substantial fraction of previously undiagnosed patients with recessive causes.

However, the scientists found that some diagnoses related to these known genes are likely not yet being made and involve DNA changes that are difficult to interpret. These findings highlight the importance of improving the interpretation of harmful genetic variants in genes known to cause disease.

Dr Kartik Chundru, first author of the study, formerly at the Wellcome Sanger Institute and now at the University of Exeter, said: “These genetic findings 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 this can lead to new diagnoses for patients without the need for additional samples.”

Dr. Vincent Ustach, lead 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 it shows the critical impact of a diverse dataset in providing a more comprehensive understanding of developmental disorders across different ancestries.

“The results of this study may generate more personalized and actionable results for families with affected children and, more broadly, improve our ability to provide responses to underrepresented populations.”

Dr Hilary Martin, lead author of the study at the Wellcome Sanger Institute, said: “One of the surprising findings of this work is that many patients with a known genetic diagnosis may in fact 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.”