title: Massively parallel sequencing of patients with intellectual disability, congenital anomalies and/or autism spectrum disorders with a targeted gene panel.
abstract: Developmental delay and/or intellectual disability (DD/ID) affects 1-3% of all children. At least half of these are thought to have a genetic etiology. Recent studies have shown that massively parallel sequencing (MPS) using a targeted gene panel is particularly suited for diagnostic testing for genetically heterogeneous conditions. We report on our experiences with using massively parallel sequencing of a targeted gene panel of 355 genes for investigating the genetic etiology of eight patients with a wide range of phenotypes including DD/ID, congenital anomalies and/or autism spectrum disorder. Targeted sequence enrichment was performed using the Agilent SureSelect Target Enrichment Kit and sequenced on the Illumina HiSeq2000 using paired-end reads. For all eight patients, 81-84% of the targeted regions achieved read depths of at least 20×, with average read depths overlapping targets ranging from 322× to 798×. Causative variants were successfully identified in two of the eight patients: a nonsense mutation in the ATRX gene and a canonical splice site mutation in the L1CAM gene. In a third patient, a canonical splice site variant in the USP9X gene could likely explain all or some of her clinical phenotypes. These results confirm the value of targeted MPS for investigating DD/ID in children for diagnostic purposes. However, targeted gene MPS was less likely to provide a genetic diagnosis for children whose phenotype includes autism.
authors.affiliation: KK Research Centre, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Maggie
authors.initials: M
authors.lastname: Brett
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: John
authors.initials: J
authors.lastname: McPherson
authors.affiliation: National Cancer Centre, Singapore, Singapore.
authors.forename: Zhi Jiang
authors.initials: ZJ
authors.lastname: Zang
authors.affiliation: Genetic Services, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Angeline
authors.initials: A
authors.lastname: Lai
authors.affiliation: Genetic Services, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Ee-Shien
authors.initials: ES
authors.lastname: Tan
authors.affiliation: Genetic Services, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Ivy
authors.initials: I
authors.lastname: Ng
authors.affiliation: Universiti Malaya Medical Centre, Petaling Jaya, Malaysia.
authors.forename: Lai-Choo
authors.initials: LC
authors.lastname: Ong
authors.affiliation: Genetic Services, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Breana
authors.initials: B
authors.lastname: Cham
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore; National Cancer Centre, Singapore, Singapore.
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.affiliation: Duke-NUS Graduate Medical School, Singapore, Singapore.
authors.forename: Steve
authors.initials: S
authors.lastname: Rozen
authors.affiliation: KK Research Centre, KK Women's & Children's Hospital, Singapore, Singapore.
authors.forename: Ene-Choo
authors.initials: EC
authors.lastname: Tan
mesh_terms: D000067877:Autism Spectrum Disorder / Q000175:diagnosis / Q000235:genetics*; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites
chemical_list: D022821:RNA Splice Sites