Genetic Study Identifies Developmental Disorders in Children

The largest ever genetic study of children with previously undiagnosed rare developmental disorders has discovered 14 new developmental disorders. The study also provided diagnoses of rare conditions for over a thousand children and their families.

There are over 1,000 recognized genetic causes, however many individual developmental disorders are so rare that the genetic causes are not known. Each year, thousands of babies are born who do not develop normally because of errors in their genetic makeup and this can lead to conditions such as intellectual disability, epilepsy, autism or heart defects.


A large team of scientists collaborating with the Wellcome Trust Sanger Institute sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analyzed these data with data from another 3,287 individuals with similar disorders. The team focused on spontaneous new mutations that arise as DNA is passed on from parents to children. The children's conditions were also clinically assessed and the team combined the results to match up children with similar disorders to provide diagnoses.

Saliva samples for the whole family and blood-extracted DNA samples for the probands were collected, processed and quality controlled. Genomic DNA was fragmented to an average size of 150 base pairs (bp) and a DNA library was created using established Illumina paired-end protocols. Adaptor-ligated libraries were amplified and indexed using polymerase chain reaction (PCR). A portion of each library was used to create an equimolar pool comprising eight indexed libraries. Enriched libraries were analyzed by 75-base paired-end sequencing.

The scientists showed that how that the most important factors influencing the diagnostic yield of damaging de novo mutations (DNMs) are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. They identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. They have also characterized the phenotypic diversity among these disorders. They estimated that 42% of their cohort carries pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function.

Jeremy McRae, PhD, the first author of the study, said, “Each of these disorders is incredibly rare, so the large number of patients in this study was crucial to diagnosis. An individual doctor may see only one case, but by collaborating with hundreds of NHS staff and researchers we were able to link children from clinics across the British Isles. This allowed the team to match up children with similar disorders within the project and provide diagnoses for them.” The study was published on January 25, 2017, in the journal Nature.