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Exome Sequencing Reveals Novel Genes Linked to Developmental Disorders

NEW YORK (GenomeWeb) – A team led by researchers from the Wellcome Trust Sanger Institute has found 14 novel genes linked to developmental disorders in children. The researchers also discovered previously unknown disorders linked to known developmental disorder-associated genes. They published their findings today in Nature.

Between 2 percent and 5 percent of children are born with major birth defects and/or exhibit severe neurodevelopmental disorders during childhood. While there are more than 1,000 recognized genetic causes that underlie development disorders, researchers believe that damaging variations in genes critical to development play a major role. However, to date it's been difficult to study.

The paper is the most recent research to come out of the UK Deciphering Developmental Disorders study.

Two hundred clinical geneticists from the UK National Health Sservice worked with the study's authors to recruit and phenotype 4,293 individuals with a severe, undiagnosed developmental disorder and their families. They performed exome sequencing of patient DNA on an Illumina HiSeq instrument, and then analyzed the data for single-nucleotide variants, insertions, and deletions.

They combined their data with analyses of 3,287 individuals with similar disorders derived from 13 published exome or genome sequencing studies.

"Each of these disorders is incredibly rare, so the large number of patients in this study was crucial to diagnosis," Jeremy McRae, first author on the study and researcher from the Wellcome Trust Sanger Institute, said in a statement. "By collaborating with hundreds of NHS staff and researchers we were able to link children from clinics across the British Isles."

After analyzing the combined data, the researchers identified 94 genes that were particularly likely to contain damaging de novo mutations not present in either parent. Fourteen of these genes had not been previously linked to developmental damage: CDK13, CHD4, CNOT3, CSNK2A1, GNAI1, KCNQ3, MSL3, PPM1D, PUF60, QRICH1, SET, KMT5B (also known as SUV420H1), TCF20, and ZBTB18.

"In addition to discovering novel [developmental disorder]-associated genes, we identified several new disorders linked to known [developmental disorder]-associated genes, but with different modes of inheritance or molecular mechanisms," the researchers wrote in the study. "We found that UPS9X and ZC4H2 had a genome-wide significant excess of [de novo mutations] in female probands, indicating that these genes have X-linked dominant modes of inheritance in addition to a previously reported X-linked recessive mode of inheritance in males."

After conducting its genetic analysis, the researchers were able to provide diagnoses of rare conditions for more than 1,000 children and their families, McRae said.

David FitzPatrick, a researcher from the MRC Human Genetics Unit at the University of Edinburgh and supervising author on the study, noted in a statement that families search for a genetic diagnosis to help them understand the cause of their child's disorder.

"This can help doctors better manage the child's condition, and gives clues for further research into future therapeutics," FitzPatrick said. "In addition to this, a diagnosis can let parents know what the future holds for their child and the risk of any subsequent pregnancies being affected with the same disorder, which can be an enormous help if they want a larger family."

Overall, the team estimated that 42 percent of the individuals studied carry a de novo mutation in protein-coding DNA sequences, which resulted in disrupted or altered gene function. The researchers also calculated that chances of a child being born with a rare developmental disorder range from 1 in 450 for 20-year old parents to 1 in 210 for 45-year old parents.