title: Next-generation sequencing in X-linked intellectual disability.
abstract: X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5-10% for X-chromosomal defects in male ID patients.
authors: Institute of Clinical Genetics, Technische Universität Dresden, Dresden, Germany.|Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Andreas
authors: A
authors: Tzschach
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Ute
authors: U
authors: Grasshoff
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Stefanie
authors: S
authors: Beck-Woedl
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Claudia
authors: C
authors: Dufke
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Claudia
authors: C
authors: Bauer
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Martin
authors: M
authors: Kehrer
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors: Christina
authors: C
authors: Evers
authors: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors: Ute
authors: U
authors: Moog
authors: Practice of Human Genetics, Homburg (Saar), Germany.
authors: Barbara
authors: B
authors: Oehl-Jaschkowitz
authors: Institute of Clinical Genetics, Technische Universität Dresden, Dresden, Germany.
authors: Nataliya
authors: N
authors: Di Donato
authors: Medical Care Center, Mönchengladbach, Germany.
authors: Robert
authors: R
authors: Maiwald
authors: Centre of Human Genetics, Mannheim, Germany.
authors: Christine
authors: C
authors: Jung
authors: Institute of Human Genetics, University Hospital Essen, Essen, Germany.
authors: Alma
authors: A
authors: Kuechler
authors: Center of Human Genetics, Jena University Hospital, Jena, Germany.
authors: Solveig
authors: S
authors: Schulz
authors: Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
authors: Peter
authors: P
authors: Meinecke
authors: Practice of Human Genetics, Bremen, Germany.
authors: Stephanie
authors: S
authors: Spranger
authors: Centre for Human Genetics, Freiburg, Germany.
authors: Jürgen
authors: J
authors: Kohlhase
authors: Practice of Pediatrics, Jena, Germany.
authors: Jörg
authors: J
authors: Seidel
authors: Practice of Medical Genetics, Dresden, Germany.
authors: Silke
authors: S
authors: Reif
authors: Practice of Medical Genetics, Dresden, Germany.
authors: Manuela
authors: M
authors: Rieger
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Angelika
authors: A
authors: Riess
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Marc
authors: M
authors: Sturm
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Julia
authors: J
authors: Bickmann
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Christopher
authors: C
authors: Schroeder
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Andreas
authors: A
authors: Dufke
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Olaf
authors: O
authors: Riess
authors: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors: Peter
authors: P
authors: Bauer
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004827:Epilepsy / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D018628:Gene Dosage; D050172:Genes, X-Linked; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D009154:Mutation; D049951:X Chromosome Inactivation / Q000235:genetics
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