oa Mutations in a zinc finger protein causing a novel autosomal recessive mental retardation syndrome identified through homozygosity mapping and whole exome sequencing of a single affected individual

A consanguineous Arab family affected by a novel autosomal recessive disorder characterized by severe mental retardation and failure to thrive, was studied by Illumina 700K SNP genotyping, candidate gene mutation screening and whole exome sequencing for one affected member. Clinical findings include ptosis, bilateral epicanthic folds, striking midface hypoplasia, downturned mouth corners, thin upper vermillion, prominent ears, bilaterally short fourth metatarsal bone, bilateral fifth finger camptodactyly, mildly limited mobility in both knees and hypotonia. The gene was mapped by homozygosity mapping to 4 possible genome intervals, as the number of family members was insufficient for a significant LOD score. The positional candidate MAP2K1 was sequenced. No pathogenic mutations were identified. Whole exome target enrichment sequencing was performed on ABI SOLiD 4 System and Illumina HiSeq platforms for a single affected individual. Six non-synonymous variants were positioned within the homozygosity intervals. Two affecting evolutionary highly conserved amino acids with damaging effects according to PolyPhen and SIFT protein-modeling software, which were validated by Sanger sequencing to determine whether variants co-segregated with the disease phenotype. The variants were absent in 188 ethnically matched control chromosomes. One gene shows very limited expression in the brain while the other, a zinc finger protein, appears to be the disease causing mutation. Zinc finger proteins, a family of DNA and RNA binding proteins are transcriptional regulators controlling developmental cascades of gene expression especially during fetal brain development. Mutations in zinc finger domains interfere with normal brain development, are associated with non-syndromic X-linked mental retardation with impairments in adaptive behavior, and manifest during the developmental period causing severe mental retardation. The c.C5054G [p.S1685W] mutation affects 2 of the 3 ZNF407 isoforms, is located in the last third of the zinc finger domains and affects a serine residue in the alpha-helical part adjoining two zinc finger domains. This is thought to eliminate the functionality of downstream domains and interferes with expression of various genes under ZNF407 control during fetal brain development. Homozygosity mapping and whole exome sequencing of a single affected individual was the most effective, least labor intensive and most economical approach in identifying the mutation for this novel autosomal recessive zinc finger protein that causes a mental retardation syndrome.