A non-consanguineous Arabic family affected by a putative novel seemingly X-linked disease characterized by mental retardation and abnormal head shape was studied by gene mapping, candidate gene mutation screening and whole X chromosome Exome sequencing of a single affected member to identify the responsible gene defect. Clinical presentation includes mental retardation, hyperactivity, hypotonia, turricephaly (in one affected), dolichocephaly (in the other affected), narrow face, downward slanted palberal fissures, large ears, open mouth appearance, long and slender fingers. Neurologic and metabolic evaluations including urine organic acid, lysosomal enzyme analysis, gaunidinocompound, CDG and Fragile-X syndrome were negative. SNP genotyping with the HumanOmniExpress bead chip [Illumina, USA], analyzed with the GeneMapper software mapped the responsible gene to four possible X-chromosome intervals [p22.33-22.2, p22.2-21.1, p31.1-q22.3, q26.3-28] as the family structure did not allow identification of a single interval with a significant LOD score. Based on the clinical presentation one candidate gene (FGF16) was screened but no pathogenic mutations were identified. Whole Exome target enrichment Next Generation Sequencing for the X chromosome was performed on the ABI SOLiD4 platform for a single affected individual. Three variants were identified within the linkage intervals: AMMECR1 [c.C208T/p.L70F] was excluded as it did not co-segregate with the disease phenotype. A second variant (c.C11T/p.P4L) in the Rab40 GTP-binding protein gene (RAB40AL). Pathogenic mutations within this gene have been associated with Martin-Probst X-linked mental retardation syndrome (MRXSMP) which presents with a different phenotype characterized by hearing loss. The last variant (c.G227A/p.C76Y) at the H2BFWT histone family gene has damaging effects according to PolyPhen and SIFT protein-modeling software, co-segregates to the disease phenotype and is absent in 752 ethnically matched control chromosomes. No known diseases have been associated with mutations in H2BFWT apart from male infertility. Tissue specific H2BFWT expression studies show expression in human fetal brain, making this mutation the likely developmental defect. At present, mutation analyses in additional healthy normal maternal male relatives are underway for the possible exclusion of H2BFWT as the offending gene.


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