New Insights into Recessive Genetic Causes of Developmental Disorders

Researchers have carried out the most extensive and varied investigation to date regarding the role that recessive genetic alterations play in developmental disorders. Their findings, which indicate that a change in research focus could increase detection rates, show that the majority of misdiagnosed cases resulting from recessive origins are connected to genes we already know about.

Scientists from the Wellcome Sanger Institute and its collaborators at GeneDx evaluated genomic data from nearly 30,000 families affected by developmental abnormalities–six times more families with higher variation in ancestral origins compared to earlier work.

Researchers found that over 80% of cases caused by recessive genetic variants are explained by known genes, even though they also discovered several genes that were previously unlinked to these conditions. Compared to prior estimates, this represents a significant increase. The study also revealed the contribution of recessive genetic variants to developmental disorders varies significantly across the ethnic groups studied.

The results, which were released in Nature Genetics throw new light on the genetic foundation of developmental problems and emphasize how crucial it is to take a person's genetic background into account when making diagnoses and conducting research.

The team argues that recent efforts to identify recessive genes linked to these disorders have mainly been successful and that the current difficulty is primarily in interpreting genetic alterations in recessive genes that are already known. According to them, employing this strategy might enable the diagnosis of twice as many patients as concentrating only on remaining gene discovery.

Numerous developmental diseases have hereditary roots and can affect a child's cognitive, behavioral, or physical development. Certain genetic conditions are recessive, meaning that a kid needs to receive a mutated copy of the gene from both parents to be affected.

These consist of Tay-Sachs disease, Bardet-Biedl syndrome, and Joubert syndrome. Thus far, there has not been any comprehensive measurement of these recessive genetic factors in a variety of populations.

In this new study, 29,745 families were identified with similar genetic origins by combining summarized data from the GeneDx cohort and the Deciphering Developmental Disorders (DDD) study. The majority of these families more than 20% of them—had non-European ancestry. This massive dataset's analysis shed new light, particularly on smaller and less researched populations.

The researchers discovered that the percentage of patients with recessive genetic variations ranged from two to 19% of cases, with a significant variation across ancestry groups. Consanguinity, or the frequency of marriages between close relatives, is closely associated with this difference among these societies.

Several newly linked genes to developmental abnormalities were found by researchers, including KBTBD2, CRELD1, and ZDHHC16. These discoveries helped families who had not previously received a diagnosis. The intricacy of these problems is further highlighted by their estimation that approximately 12.5% of individuals may have numerous hereditary variables contributing to their condition.

Crucially, they discovered that 84% of instances resulting from recessive genetic variants are explained by known genes, and this percentage was consistent for people with and without European ancestry.

This significant rise above earlier estimates indicates that a significant portion of patients with recessive causes who were previously undetected may have novel recessive genes that have been found in recent years. The researchers did discover, however, that there are probably still diagnoses involving difficult-to-interpret DNA alterations in these recognized genes that are being overlooked.

The results highlight how critical it is to enhance the understanding of deleterious genetic variations in genes that are known to cause disease.

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. Kartik Chundru, Study First Author, University of Exeter

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.”

One of the surprising findings from this work was that many patients with one known genetic diagnosis might 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.”

Dr. Hilary Martin, Study Senior Author, Wellcome Sanger Institute