title: Exome sequencing circumvents missing clinical data and identifies a BSCL2 mutation in congenital lipodystrophy.
abstract: BACKGROUND
  Exome sequencing has become more and more affordable and the technique has emerged as an important diagnostic tool for monogenic disorders at early stages of investigations, in particular when clinical information is limited or unspecific as well as in cases of genetic heterogeneity.
  
  
  METHODS
  We identified a consanguineous Pakistani family segregating an autosomal recessive phenotype characterized by muscular hypertrophy, mild mental retardation and skeletal abnormalities. The available clinical information was incomplete and we applied whole exome sequencing in an affected family member for the identification of candidate gene variants.
  
  
  RESULTS
  Exome sequencing identified a previously unreported homozygous mutation in the acceptor splice site of intron 5 in the BSCL2 gene (c.574-2A > G). Expression analysis revealed that the mutation was associated with skipping of exon 6. BSCL2 mutations are associated with Berardinelli-Seip congenital lipodystrophy and a clinical re-evaluation of affected individuals confirmed the diagnosis.
  
  
  CONCLUSIONS
  Exome sequencing is a powerful technique for the identification of candidate gene variants in Mendelian traits. We applied this technique on a single individual affected by a likely autosomal recessive disorder without access to complete clinical details. A homozygous and truncating mutation was identified in the BSCL2 gene suggesting congenital generalized lipodystrophy. Incomplete phenotypic delineations are frequent limiting factors in search for a diagnosis and may lead to inappropriate care and follow-up. Our study exemplifies exome sequencing as a powerful diagnostic tool in Mendelian disorders that may complement missing clinical information and accelerate clinical diagnosis.
authors: Jens
authors: J
authors: Schuster
authors: Tahir Naeem
authors: TN
authors: Khan
authors: Muhammad
authors: M
authors: Tariq
authors: Pakeeza Arzoo
authors: PA
authors: Shaiq
authors: Katrin
authors: K
authors: Mäbert
authors: Shahid Mahmood
authors: SM
authors: Baig
authors: Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala, Sweden. joakim.klar@igp.uu.se.
authors: Joakim
authors: J
authors: Klar
mesh_terms: D003241:Consanguinity; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics*; D015870:Gene Expression; D023061:Gene Order; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D052497:Lipodystrophy, Congenital Generalized / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D022821:RNA Splice Sites
chemical_list: C432679:BSCL2 protein, human; D044388:GTP-Binding Protein gamma Subunits; D022821:RNA Splice Sites