Research Reveals 28 New Genes Associated with Rare Developmental Disorders

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[Wellcome Sanger Institute, Genome Research Ltd.]

Research led by the Wellcome Sanger Institute near Cambridge has identified 28 new genes that are associated with developmental disorders in children, which the team thinks could lead to new diagnoses for around 500 families.

Around the world there are approximately 400,000 babies born each year with rare developmental disorders caused by spontaneous, non-inherited gene mutations. These disorders can have an intellectual impact and also cause conditions such as epilepsy, autism or heart problems.

Although a few hundred of the genes linked with these disorders have been identified, as many as 1000 have not, according to the researchers. This causes problems for families with affected children, many of whom do not receive a diagnosis. Indeed, up to 60% of all children with developmental disorders do not get a diagnosis and of this group it is estimated that half may have a mutation in as yet unidentified genes.

“Caring for a child with a developmental disorder can be extremely challenging for a family, particularly when their child’s doctors don’t know what is causing their condition and are unable to make a diagnosis. A diagnosis can help families to access support networks, inform treatment for their child and help them to understand the risk for any further children they might have,” said Helen Firth, M.D., Consultant Clinical Geneticist at Addenbrooke’s Hospital in Cambridge who was involved in the study.

Matthew Hurles, Ph.D., Head of Human Genetics at the Sanger Institute, Firth, and researchers from around the UK, the Netherlands and the US carried out a large analysis of healthcare and exome sequencing data from 31,058 children with a developmental disorder and their parents to search for causative genes.

In addition to 285 previously identified genes linked with these conditions, Hurles and team discovered 28 genes that had not previously been strongly linked to developmental disorders accounting for around 1% of the cohort.

Some of the gene variants that cause these disorders have incomplete penetrance – some individuals carry them, but do not express the traits associated with the mutation – which lowers the ability of the researchers to detect them. Pre- or perinatal death of the affected infants also impacts the chance of the mutation being detected, according to the team.

Hurles and colleagues estimate that finding the 1000 additional genes predicted to be responsible for a large proportion of these disorders will require significantly more data than what is currently available.

“Our findings estimate that we require ten times as much data to be able to identify all the genes linked to developmental disorders,” explained Hurles, which would mean a minimum of 350,000 parent–offspring trios.

“As such, greater access to anonymized patient data is crucial to our understanding of these conditions and our ability to help the families living with them.”

Discussing the results in their recent Nature paper, the researchers write that “most of the increased power to detect novel disorders comes from the increase in sample size, rather than the improved statistical test.”

They add that although there are many more genes still to be discovered, the inclusion of the 28 additional genes confirmed in this study in diagnostic tests will help to improve diagnoses of developmental conditions around the world.

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