title: A novel APC mutation defines a second locus for Cenani-Lenz syndrome.
abstract: BACKGROUND
  Cenani-Lenz syndrome (CLS) is an autosomal recessive condition characterised by a unique pattern of syndactyly, and variable penetrance of renal agenesis and facial dysmorphism. LRP4 mutations were identified in most, but not all patients with this syndrome, suggesting the presence of at least one additional locus.
  
  
  METHODS
  Clinical characterisation of a new CLS family followed by autozygosity mapping, whole-exome sequencing and global gene expression profiling.
  
  
  RESULTS
  We describe an extended consanguineous Saudi family with typical CLS features in addition to significant scoliosis. The disease in this family maps to a single autozygous interval on 5q22.2, in which whole-exome sequencing revealed the presence of a novel splicing mutation in APC that results in ∼ 80% reduction of the wild-type transcript and the creation of an aberrant transcript that predicts a severely truncated APC. This was found to be associated with upregulation of Wnt/β-catenin signalling.
  
  
  CONCLUSIONS
  In a pattern similar to how LRP4 mutations are predicted to negate the protein's antagonistic effect on Wnt/β-catenin signalling, we propose that reduction of APC may increase the availability of β-catenin by virtue of impaired degradation, leading to a similar phenotypic outcome. This is the first time APC is linked to a human phenotype distinct from its established role in oncology.
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Nisha
authors: N
authors: Patel
authors: Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia.
authors: Eissa
authors: E
authors: Faqeih
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Shams
authors: S
authors: Anazi
authors: Spine Department, King Fahad Medical City, Riyadh, Saudi Arabia.
authors: Mohammad
authors: M
authors: Alfawareh
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Salma M
authors: SM
authors: Wakil
authors: Department of Biostatistics and Scientific Computing, Epidemiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors: Dilek
authors: D
authors: Colak
authors: Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
authors: Fowzan S
authors: FS
authors: Alkuraya
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D017398:Alternative Splicing; D002874:Chromosome Mapping; D003241:Consanguinity; D059472:Exome; D019066:Facies; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D023061:Gene Order; D053263:Gene Regulatory Networks; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D040641:Quantitative Trait Loci; D013576:Syndactyly / Q000175:diagnosis / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051176:beta Catenin
keywords: LRP4; scoliosis; syndactyly; β-catenin