title: Affected kindred analysis of human X chromosome exomes to identify novel X-linked intellectual disability genes.
abstract: X-linked Intellectual Disability (XLID) is a group of genetically heterogeneous disorders caused by mutations in genes on the X chromosome. Deleterious mutations in ~10% of X chromosome genes are implicated in causing XLID disorders in ~50% of known and suspected XLID families. The remaining XLID genes are expected to be rare and even private to individual families. To systematically identify these XLID genes, we sequenced the X chromosome exome (X-exome) in 56 well-established XLID families (a single affected male from 30 families and two affected males from 26 families) using an Agilent SureSelect X-exome kit and the Illumina HiSeq 2000 platform. To enrich for disease-causing mutations, we first utilized variant filters based on dbSNP, the male-restricted portions of the 1000 Genomes Project, or the Exome Variant Server datasets. However, these databases present limitations as automatic filters for enrichment of XLID genes. We therefore developed and optimized a strategy that uses a cohort of affected male kindred pairs and an additional small cohort of affected unrelated males to enrich for potentially pathological variants and to remove neutral variants. This strategy, which we refer to as Affected Kindred/Cross-Cohort Analysis, achieves a substantial enrichment for potentially pathological variants in known XLID genes compared to variant filters from public reference databases, and it has identified novel XLID candidate genes. We conclude that Affected Kindred/Cross-Cohort Analysis can effectively enrich for disease-causing genes in rare, Mendelian disorders, and that public reference databases can be used effectively, but cautiously, as automatic filters for X-linked disorders.
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America.
authors: Tejasvi S
authors: TS
authors: Niranjan
authors: Greenwood Genetic Center, Greenwood, South Carolina. 29646, United States of America.
authors: Cindy
authors: C
authors: Skinner
authors: Greenwood Genetic Center, Greenwood, South Carolina. 29646, United States of America.
authors: Melanie
authors: M
authors: May
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America; Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America; Department of Genomic Sciences, University of Washington, Seattle, Washington 98195, United States of America.
authors: Tychele
authors: T
authors: Turner
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America.
authors: Rebecca
authors: R
authors: Rose
authors: Greenwood Genetic Center, Greenwood, South Carolina. 29646, United States of America.
authors: Roger
authors: R
authors: Stevenson
authors: Greenwood Genetic Center, Greenwood, South Carolina. 29646, United States of America.
authors: Charles E
authors: CE
authors: Schwartz
authors: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States of America.
authors: Tao
authors: T
authors: Wang
mesh_terms: D041321:Chromosomes, Human, X / Q000235:genetics*; D015331:Cohort Studies; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA