PMC3918143_01
Clinical and genetic characterization of the consanguineous Egyptian family described herein. A Pedigree. II:1 is depicted in grey because she likely had the same disorder as II:4 but was never seen by the investigators. M, mutant WWOX allele; WT, wildtype WWOX allele. B Patient II:4 with microcephaly and facial dysmorphism (bitemporal narrowing, high forehead, epicanthic folds, broad base of nose, long philtrum). C Sanger sequencing confirmed the homozygous WWOX mutation in exon 2, c.160G > T (p.Arg54*) in II:4 (upper panel). Middle: Heterozygosity as seen in both parents and II:3, lower panel: Wildtype sequence in the healthy brother. D Scheme of the human WWOX gene (vertical bars: exons) and cartoon of the WWOX protein with two WW domains and the short-chain alcohol dehydrogenase/reductase domain. The position of the human mutation (red) and the position corresponding to the rat frameshift mutation (c.1110_1122del/p.Leu371Thrfs*41) are given.
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F1
Only five variants were predicted as deleterious by all or most programs and localized to LOH regions, including a gained stop codon in WWOX (WW domain containing oxidoreductase) that localizes in exon 2 and affects codon 54 for arginine (c.160G > T; p.Arg54*) in the largest LOH region identified (54 Mb) (chr16:25,457,305-79,894,309; GRCh37) [Additional file 1: Figure S1]. The healthy brother (II:2) was homozygous for the wildtype allele (Figure 1C).