Most recessive developmental disorders linked to known gene variants

Most inherited developmental disorders are caused by previously identified genetic variants, according to the largest and most diverse study to date.

Using newer techniques, researchers at the Wellcome Sanger Institute, near Cambridge, and GeneDx, Maryland, reanalysed genetic data from almost 30,000 families affected by autosomal recessive developmental disorders (ARDD) to better understand their genetic causes. The team found that 84 percent of genetic changes were in known ARDD-related genes, but nearly 35 percent of mutations in those genes had not been previously identified as disease-causing.

'These gene discoveries will provide answers for some previously undiagnosed families and help clinicians better understand and identify these conditions,' said Dr Kartik Chundru, first author of the study published in Nature Genetics, formerly at the Wellcome Sanger Institute and now at the University of Exeter Medical School.

Dr Chundru added, 'Our study highlights the importance of reanalysing genetic data with updated methods and knowledge, as it can lead to new diagnoses for patients without needing additional samples.'

Combining exome sequencing data from the Deciphering Developmental Disorders study and GeneDx cohorts, the team split a total of 29,745 families into 22 different ancestral groups. They found that the number of patients affected by ARDD genes differed by ancestry, ranging from two to 19 percent of cases. The authors attributed this to differing rates of consanguinity, which describes a relationship between two people who share an ancestor.

While the data indicate that most genetic changes occurred in previously identified ARDD genes, the team also discovered new genes – KBTBD2 and ZDHHC16 – which may provide answers to families awaiting diagnoses. They also estimate that around 12.5 percent of patients have an additional, non-inherited, genetic alteration contributing to their condition.

Senior author of the study and group leader at the Wellcome Sanger Institute, Dr Hilary Martin, 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.'

Dr Martin added, 'Identifying these additional changes could improve our understanding of the patient's condition, lead to more accurate diagnoses, and potentially offer new treatment options.'