Combination of Linkage Mapping and Microarray-Expression Analysis Identifies NF-κB Signaling Defect as a Cause of Autosomal-Recessive Mental Retardation

Autosomal-recessive inheritance accounts for nearly 25% of nonsyndromic mental retardation (MR), but the extreme heterogeneity of such conditions markedly hampers gene identification. Combining autozygosity mapping and RNA expression profiling in a consanguineous Tunisian family of three MR children with mild microcephaly and white-matter abnormalities identified the TRAPPG9 gene, which encodes a NF-kappa B-inducing kinase (NIK) and I kappa B kinase complex beta (IKK-beta) binding protein, as a likely candidate. Sequencing analysis revealed a nonsense variant (c.1708C>T [p.RS70X]) within exon 9 of this gene that is responsible for an undetectable level of TRAPPC9 protein in patient skin fibroblasts. Moreover, TNF-alpha stimulation assays showed a defect in IkB alpha degradation, suggesting impaired NF-kappa B signaling in patient cells. This study provides evidence of an NF-kappa B signaling defect in isolated MR.