Abstract : Background: A consanguineous Arab family is affected by an apparently novel autosomal recessive disordercharacterized by cognitive impairment, failure-to-thrive, hypotonia and dysmorphic features including bilateral ptosisand epicanthic folds, synophrys, midface hypoplasia, downturned mouth corners, thin upper vermillion border andprominent ears, bilateral 5th finger camptodactyly, bilateral short 4th metatarsal bones, and limited knee mobilitybilaterally.
Methods:The family was studied by homozygosity mapping, candidate gene mutation screening and wholeExome 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 wasidentified in theZNF407gene at 18q23. The Serine to Tryptophane mutation affects two of the three ZNF407isoforms 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 thetwo fingers, leading to a higher flexibility of the linker and thus to a decreased probability of binding to the targetDNA sequence essentially eliminating the functionality of downstream domains and interfering with the expressionof various genes under ZNF407 control during fetal brain development.
Conclusions:ZNF407 is a transcription factor with an essential role in brain development. When specific andlimited in number homozygosity intervals exist that harbor the offending gene in consanguineous families, WholeExome Sequencing of a single affected individual is an efficient approach to gene mapping and mutationidentification.
