Journal Article

Prevalence and architecture of de novo mutations in developmental disorders

Kelsell, Rosemary, Mugalaasi, Hood, Price, Sue, Kivuva, Emma, Stewart, Helen, Newbury-Ecob, Ruth, Sheridan, Eamonn, Kingston, Helen, McNerlan, Susan, Dabir, Tabib, Suri, Mohnish, McKay, Kirsten, Jarvis, Joanna, Cross, Gareth, Bitner-Glindzicz, Maria, Bunyan, David J, Ross, Alison, Seller, Anneke, Dean, John, He, Liu, King, Daniel, Singzon, Roldan, Donaldson, Alan, Kirk, Claire, Sandford, Richard, Hildyard, Lucy, Hutton, Ben, Williams, Nicola, Blair, Edward, Singh, Tarjinder, Dobbie, Angus, Fendick, Tina, Lim, Derek, Miles, Emma, Hurles, Matthew E, Pilz, Daniela T, Murday, Victoria, Temple, I. Karen, Hawkins, Rose, Hollingsworth, Georgina, Ghali, Neeti, Park, Soo-Mi, Donnelly, Deirdre, Connell, Fiona, Fry, Andrew, Robert, Leema, Balasubramanian, Meena, Sampson, Julian, Fisher, Richard, Anjum, Uruj, Rankin, Julia, Jenkins, Lucy, Alvi, Mohsan, Ong, Kai-Ren, Lees, Melissa, Irving, Melita, Murphy, Helen, Payne, Stewart, Weber, Astrid, Taylor, Cat, McWilliam, Catherine, Deshpande, Charu, Mansour, Sahar, McConnell, Vivienne, Moore, David, Pratt, Norman, Davidson, Rosemarie, Wright, Caroline F, McEntagart, Meriel, Henderson, Ale

2017

Overview

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year. Whole-exome analysis of individuals with developmental disorders shows that de novo mutations can equally cause loss or altered protein function, but that most mutations causing altered protein function have not yet been described. De novo mutations in developmental disorders Matthew Hurles, Jeremy McRae and colleagues from the Deciphering Developmental Disorders Study report exome sequencing of 4,293 families containing individuals with severe, undiagnosed developmental disorders. They find enrichment of damaging de novo mutations in 94 genes, implicating them in developmental disorders. They estimate that 42% of the cohort carry pathogenic de novo mutations in coding sequences resulting in disrupted or altered protein function.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/2489 / 631/208/737 / 692/699/375 / Adolescent / Adult / Age / Autoantigens - genetics / Births / Casein Kinase II - genetics / Causality / CDC2 Protein Kinase - genetics / Child / Chromosomal Proteins, Non-Histone / Cohort Studies / DEAD-box RNA Helicases - genetics / Developmental disabilities / Developmental Disabilities - genetics / Distribution / DNA-Binding Proteins - genetics / Estimates / Exome - genetics / Families & family life / Female / Genes / Genetic aspects / Genetic disorders / Genomes / Heredity - genetics / Histone-Lysine N-Methyltransferase - genetics / Homeodomain Proteins - genetics / Humanities and Social Sciences / Humans / Male / Mi-2 Nucleosome Remodeling and Deacetylase Complex - genetics / Middle Aged / multidisciplinary / Mutation / Mutation - genetics / Myeloid-Lymphoid Leukemia Protein - genetics / Nerve Tissue Proteins - genetics / Parents / Phenotype / Prevalence / Protein Phosphatase 2C - genetics / ras GTPase-Activating Proteins - genetics / Repressor Proteins - genetics / Science / Sequence Analysis, DNA / Sex Characteristics / Transcription Factors - genetics / Young Adult