title: Mutations in zinc finger 407 [ZNF407] cause a unique autosomal recessive cognitive impairment syndrome.
abstract: BACKGROUND
  A consanguineous Arab family is affected by an apparently novel autosomal recessive disorder characterized by cognitive impairment, failure-to-thrive, hypotonia and dysmorphic features including bilateral ptosis and epicanthic folds, synophrys, midface hypoplasia, downturned mouth corners, thin upper vermillion border and prominent ears, bilateral 5th finger camptodactyly, bilateral short 4th metatarsal bones, and limited knee mobility bilaterally.
  
  
  METHODS
  The family was studied by homozygosity mapping, candidate gene mutation screening and whole Exome Next Generation Sequencing of a single affected member to identify the offending gene and mutation. The mutated gene product was studied by structural bioinformatics methods.
  
  
  RESULTS
  A damaging c.C5054G mutation affecting an evolutionary highly conserved amino acid p.S1685W was identified in the ZNF407 gene at 18q23. The Serine to Tryptophane mutation affects two of the three ZNF407 isoforms and is located in the last third of the protein, in a linker peptide adjoining two zinc-finger domains. Structural analyses of this mutation shows disruption of an H-bond that locks the relative spatial position of the two fingers, leading to a higher flexibility of the linker and thus to a decreased probability of binding to the target DNA sequence essentially eliminating the functionality of downstream domains and interfering with the expression of various genes under ZNF407 control during fetal brain development.
  
  
  CONCLUSIONS
  ZNF407 is a transcription factor with an essential role in brain development. When specific and limited in number homozygosity intervals exist that harbor the offending gene in consanguineous families, Whole Exome Sequencing of a single affected individual is an efficient approach to gene mapping and mutation identification.
authors.forename: Marios
authors.initials: M
authors.lastname: Kambouris
authors.forename: Rachid C
authors.initials: RC
authors.lastname: Maroun
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.forename: Yasser
authors.initials: Y
authors.lastname: Al-Sarraj
authors.forename: Khaoula
authors.initials: K
authors.lastname: Errafii
authors.forename: Rehab
authors.initials: R
authors.lastname: Ali
authors.forename: Hala
authors.initials: H
authors.lastname: Boulos
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Curmi
authors.affiliation: Qatar Biomedical Research Institute, Medical Genetics Center, 69 Lusail Street, West Bay Area, P,O, Box: 33123, Doha, Qatar. elshantih@smgc.org.qa.
authors.forename: Hatem
authors.initials: H
authors.lastname: El-Shanti
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000595:Amino Acid Sequence; D002648:Child; D003072:Cognition Disorders / Q000235:genetics*; D005808:Genes, Recessive; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017386:Sequence Homology, Amino Acid; D013577:Syndrome; D016335:Zinc Fingers / Q000235:genetics*