Figure 1.

Mutations in CCDC8 Cause 3-M Syndrome

(A) Individuals with 3-M syndrome who have CCDC8 mutations: i) 3M-2, ii) 3M-5. Their phenotype is indistinguishable from individuals with CUL7 or OBSL1 mutations.

(B) Region of homozygosity on chromosome 19 common to three affected consanguineous individuals from different families. Analysis of SNP data from the Affymetrix Genome-Wide Human SNP Array 6.0 was performed by AutoSNPa. Black and yellow bars indicate homozygous and heterozygous SNP calls, respectively. Isolated heterozygous SNP calls within the larger homozygous region are likely to correspond to missed calls. The region of common homozygosity is flanked by recombinants at rs535840 located at 45,373,227 bp and rs1991722 located at 53,270,701 bp, as shown by the red boxes.

(C) Schematic of the third 3-M syndrome critical region and identity of CCDC8 mutations. Shown is a genetic map of chromosome 19 highlighting the critical region located between rs535840 and rs1991722 and the relative location of CCDC8 within the region. CCDC8 is a single-exon gene encoding a protein of 538 amino acids, and bioinformatic analysis has indicated a coiled-coil domain located between residues 349–369 and 513–535 and an alanine-rich domain located between residues 299 and 471. Location and chromatograms of mutations in CCDC8 in individuals with 3-M syndrome are indicated by arrows.