ClinVar

In 5 Mennonite patients with autosomal recessive intellectual developmental disorder-34 with variant lissencephaly (MRT34; 614499), Puffenberger et al. (2012) identified a homozygous 382G-C transversion in the CRADD gene, resulting in a gly128-to-arg (G128R) substitution in a highly conserved residue in the CRADD death domain. The mutation was found by homozygosity mapping followed by exome sequencing. Seven heterozygous carriers of this mutation were found among 203 Mennonite control samples, yielding a population-specific allele frequency of 1.72%. (Puffenberger (2012) stated that the correct population-specific allele frequency data appear in Table 4; corresponding data in the text are incorrect.) Overexpression of mutant murine Cradd with the G128R mutation showed normal protein localization to the nucleus and cytoplasm. However, when co-overexpressed with wildtype Pidd (605247), mutant G128R Cradd formed large cytoplasmic aggregates with a relative loss of Cradd expression in the nucleus. The findings suggested that the G128R mutation alters 1 of the interaction surfaces of the CRADD death domain to decrease affinity for the PIDD death domain.

In 2 Mennonite sisters (family LR04-101) with MRT34 with thin lissencephaly, Di Donato et al. (2016) identified homozygosity for the same c.382G-C transversion (rs387906861) in the CRADD gene that had been identified in a Mennonite family (LR15-293) by Puffenberger et al. (2012). The mutation, which was found by whole-exome sequencing, was present at a low frequency in the ExAC database (0.000008).