By contrast, neither of the two truncating variants in ITIH5L segregated completely with mental retardation (Table 3 and Supplementary Fig. 1). We analyzed the complete coding sequence of ITIH5L in controls and found one of the truncating variants previously observed in a subject with mental retardation. The lack of segregation with mental retardation, the presence of a truncating variant in normal controls and the recent finding of a likely mental retardation–causing IL1RAPL1 deletion in one family with an ITIH5L truncating variant (unpublished data, Table 3) suggests that truncating variants in ITIH5L are not the cause of mental retardation in the families in which they were identified. Nevertheless, the strong evidence overall for the role in mental retardation of genes with more than one nonrecurrent truncating variant is reflected in the heterogeneity lod score of 18.3, with an estimated 92% families in this subset due to the truncating variant.
