TY - JOUR
T1 - Genome sequencing identifies major causes of severe intellectual disability
AU - Gilissen, Christian
AU - Hehir-Kwa, Jayne Y.
AU - Thung, Djie Tjwan
AU - van de Vorst, Maartje
AU - van Bon, Bregje W. M.
AU - Willemsen, Marjolein H.
AU - Kwint, Michael
AU - Janssen, Irene M.
AU - Hoischen, Alexander
AU - Schenck, Annette
AU - Leach, Richard
AU - Klein, Robert
AU - Tearle, Rick
AU - Bo, Tan
AU - Pfundt, Rolph
AU - Yntema, Helger G.
AU - de Vries, Bert B. A.
AU - Kleefstra, Tjitske
AU - Brunner, Han G.
AU - Vissers, Lisenka E. L. M.
AU - Veltman, Joris A.
PY - 2014/7/17
Y1 - 2014/7/17
N2 - Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin(1,2). The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed(3-6). Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
AB - Severe intellectual disability (ID) occurs in 0.5% of newborns and is thought to be largely genetic in origin(1,2). The extensive genetic heterogeneity of this disorder requires a genome-wide detection of all types of genetic variation. Microarray studies and, more recently, exome sequencing have demonstrated the importance of de novo copy number variations (CNVs) and single-nucleotide variations (SNVs) in ID, but the majority of cases remain undiagnosed(3-6). Here we applied whole-genome sequencing to 50 patients with severe ID and their unaffected parents. All patients included had not received a molecular diagnosis after extensive genetic prescreening, including microarray-based CNV studies and exome sequencing. Notwithstanding this prescreening, 84 de novo SNVs affecting the coding region were identified, which showed a statistically significant enrichment of loss-of-function mutations as well as an enrichment for genes previously implicated in ID-related disorders. In addition, we identified eight de novo CNVs, including single-exon and intra-exonic deletions, as well as interchromosomal duplications. These CNVs affected known ID genes more frequently than expected. On the basis of diagnostic interpretation of all de novo variants, a conclusive genetic diagnosis was reached in 20 patients. Together with one compound heterozygous CNV causing disease in a recessive mode, this results in a diagnostic yield of 42% in this extensively studied cohort, and 62% as a cumulative estimate in an unselected cohort. These results suggest that de novo SNVs and CNVs affecting the coding region are a major cause of severe ID. Genome sequencing can be applied as a single genetic test to reliably identify and characterize the comprehensive spectrum of genetic variation, providing a genetic diagnosis in the majority of patients with severe ID.
U2 - 10.1038/nature13394
DO - 10.1038/nature13394
M3 - Article
C2 - 24896178
SN - 0028-0836
VL - 511
SP - 344
EP - 347
JO - Nature
JF - Nature
IS - 7509
ER -