Wellcome Sanger Institute researchers uncover new clues about childhood diseases

PUBLISHED: 19:00 05 April 2018 | UPDATED: 19:00 05 April 2018

Patrick Short, at the Wellcome Trust Sanger Institute, Hinxton

Patrick Short, at the Wellcome Trust Sanger Institute, Hinxton

Iliffe Media Ltd

Mutations outside genes can cause developmental disorders, they find

Matthew Hurles, of Wellcome Trust Sanger Institute. Picture: Stephen BondMatthew Hurles, of Wellcome Trust Sanger Institute. Picture: Stephen Bond

A study of 8,000 families led by scientists at Wellcome Sanger Institute has uncovered new clues about undiagnosed childhood diseases.

The researchers found for the first time that mutations outside of genes can cause developmental disorders of the central nervous system.

Thousands of babies are born every year in the UK with errors in their DNA that mean they do not develop normally. The genetic changes can lead to intellectual disabilities, epilepsy, autism or heart defects.

But many developmental disorders are so rare they remain undiagnosed.

The Deciphering Developmental Disorders (DDD) Study was launched in 2010 to find diagnoses for children with unknown diseases using genomics.

The study has involved more than 13,000 children but two-thirds of the families are still without answers.

Now, in the latest study, Sanger Institute scientists investigated genetic disorders of the central nervous system, such as developmental brain dysfunction, which can lead to impaired learning and language.

Studying the genomes of almost 8,000 child and parent trios, they focused on genes that coded for proteins as well as non-coding parts of the genome, which control the switching on or off of genes. These parts are known as regulatory elements.

The researchers discovered that mutations in these regulatory elements outside genes can cause neurodevelopmental disorders.

Throughout mammalian evolutionary history, regulatory elements have remained largely unchanged, or very highly ‘conserved’, which suggests they play a key role in early brain development.

Patrick Short, first author from the Wellcome Sanger Institute, said: “For the first time, we’ve been able to say how many children with severe neurodevelopmental disorders have damaging genetic changes in parts of the genome called regulatory elements.

“Of the near 8,000 families we studied, up to 140 children are likely to have these particular mutations that are responsible for their condition. We’re getting closer to providing a diagnosis for these families.

“For the first time, we’ve been able to say how many children with severe neurodevelopmental disorders have damaging genetic changes in parts of the genome called regulatory elements.

Of the near 8,000 families we studied, up to 140 children are likely to have these particular mutations that are responsible for their condition. We’re getting closer to providing a diagnosis for these families.”

Understand the mechanism by which the mutations cause neurodevelopmental disorders requires linking the mutated regulatory elements to the genes they target. This is challenging as genes and the elements that regulate their expression are often located far apart in the genome.

Dr Matthew Hurles, leader of the DDD study and lead author from the Wellcome Sanger Institute, said: “In order to be able to give a genetic diagnosis for these children with neurodevelopmental disorders, we must first associate individual regulatory elements with specific disorders.

“This will be made possible, in part, by involving larger numbers of families in our studies. Data from the NHS 100,000 Genomes Project, being delivered by Genomics England, could be crucial in providing additional evidence to allow us to define these disorders with sufficient precision to allow diagnoses to be made.”

Professor Anneke Lucassen, chair of the British Society of Genetic Medicine, said: “This study is a promising step towards providing the answers that families have been seeking for years. Once these families receive a diagnosis, they will be able to make decisions about the treatment options for their child and make future plans for their family.”

The work, published in Nature, was supported by the Health Innovation Challenge Fund, a parallel funding partnership between Wellcome and the UK Department of Health, the Wellcome Sanger Institute, and the MRC Human Genetics Unit programme.

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