title: Targeted next generation sequencing reveals a novel intragenic deletion of the TPO gene in a family with intellectual disability.
abstract: OBJECTIVE
  Next generation sequencing (NGS) approaches have revolutionized the identification of mutations underlying genetic disorders. This technology is particularly useful for the identification of mutations in known and new genes for conditions with extensive genetic heterogeneity. In the present study we investigated a consanguineous Pakistani family with intellectual disability (ID).
  
  
  METHODS
  Genotyping was carried out using 250k and 6k SNP microarrays in order to perform homozygosity mapping and copy number variation (CNV) analysis. Targeted NGS was performed to identify the genetic defect in this family. qPCR was performed to validate and confirm the NGS result.
  
  
  RESULTS
  Homozygosity mapping positioned the causative defect on chromosome 2p25.3-p25.2. Subsequent targeted NGS revealed an intragenic deletion of five exons of the gene TPO.
  
  
  CONCLUSIONS
  NGS is a powerful method to uncover submicroscopic structural variations. This result demonstrates that an unbiased screening approach such as NGS can help to identify even unexpected disease-causing mutations.
authors.affiliation: Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Attia
authors.initials: A
authors.lastname: Razzaq
authors.forename: Mohsin
authors.initials: M
authors.lastname: Shahzad
authors.forename: Muhammad Yasir
authors.initials: MY
authors.lastname: Zahoor
authors.forename: Muhammad
authors.initials: M
authors.lastname: Qasim
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Nienke
authors.initials: N
authors.lastname: Wieskamp
authors.forename: Michael P
authors.initials: MP
authors.lastname: Kwint
authors.forename: Sabine
authors.initials: S
authors.lastname: Gijsen
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Sheikh
authors.initials: S
authors.lastname: Riazuddin
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D002874:Chromosome Mapping; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics*; D003241:Consanguinity; D005091:Exons / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics / Q000523:psychology; D008607:Intellectual Disability / Q000235:genetics*; D007453:Iodide Peroxidase / Q000235:genetics*; D008297:Male; D010154:Pakistan; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA / Q000379:methods*; D017384:Sequence Deletion
chemical_list: D007453:Iodide Peroxidase