3-M Syndrome via the CCDC8 Gene

3-M syndrome is an intrauterine growth retardation disorder characterized by pre and postnatal growth retardation, a large head circumference, and a characteristic facial appearance including a prominent forehead, pointed triangular shaped face, a short upturned nose with anteverted nares, prominent mouth and lips and full eyebrows (van der Wal et al. 2001; Marik et al. 2002; Huber et al. 2005). Additional findings include a short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, slender long bones with diaphyseal constriction, tall vertebral bodies, delayed bone age and prominent heels (van der Wal et al. 2001; Huber et al. 2005; Huber et al. 2009). 3-M syndrome is currently known to be caused by pathogenic variants in the CUL7, OBSL1 and CCDC8 genes. CUL7 and OBSL1 are responsible for 77.5% and 16.3% of 3-M syndrome cases, respectively (AL-Dosari et al. 2012), while CCDC8 pathogenic variants were reported in only a few 3-M syndrome families (AL-Dosari et al. 2012; Hanson et al. 2011).

3-M syndrome is an autosomal recessive disorder caused by pathogenic variants in the CUL7, OBSL1 and CCDC8 genes (Al-Dosari et al. 2012). The CCDC8 gene encodes the coiled-coil domain-containing protein, which partners with CUL7 and OBSL1 to form a 3-M complex to maintain microtubule and genome integrity (Yan et al. 2014). Only three unique CCDC8 pathogenic variants have been reported, and all three variants lead to premature protein termination c.84dupT (p.Lys29*); c.612dupG (p.Lys205Glufs*59) and c.803_807delAGATCinsT (p.Lys268Ilefs*40). The c.612dupG (p.Lys205Glufs*59) variant was found in four consanguineous South Asian 3-M families (Hanson et al. 2011).

This test provides full coverage of all coding exons of the CCDC8 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Due to limited publications, clinical sensitivity is difficult to predict. The mutation detection rate by sequencing should be high because the three known unique pathogenic variants are missense, nonsense and a small deletion.