Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) Syndrome via the CTDP1 Gene

Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is a complex developmental disorder that affects multiple organs and tissues, generally during intra-uterine development. Primary diagnostic criteria includes bilateral congenital cataracts, which is the first and invariable presenting sign, microcornea, microphthalmos, micropupils, developmental delay, small stature and low weight, hypo/demyelinating neuropathy, mild facial dysmorphism (develops in late childhood), and mild hypogonadism. Additional features include mild cognitive deficit, cerebral and spinal cord atrophy on neuroimaging, post-infectious rhabdomyolysis, and osteoporosis (Kalaydjieva and Chamova 2014; Kalaydjieva 2006).

Autosomal recessive Congenital Cataracts Facial Dysmorphism Neuropathy (CCFDN) syndrome is caused by the homozygous founder mutation c.863+389C>T in an antisense Alu element in intron 6 of the CTDP1 gene (Varon et al. 2003; Lassuthova et al. 2014). RT–PCR and sequencing analysis have shown that this deep intronic sequence variant results in aberrant splicing and an insertion of 95 nucleotides of the Alu sequence in the processed CTDP1 transcript. Both the wild-type (WT) and mutant transcripts were present in all cells from individuals with CCFDN, indicating that the mutation causes partial deficiency. However, the levels of the WT transcript in cells from individuals with CCFDN were 15–35% of those in control cells. CTDP1 encodes the protein phosphatase FCP1, which is an essential component of the eukaryotic transcription machinery (Varon et al. 2003).

CTDP1 mutation screening in 887 unaffected population controls (105 non-Gypsy Europeans and 782 individuals of Gypsy ethnicity from Bulgaria representing 13 different Gypsy groups) found a 6.9% carrier rate among the Rudari, an average carrier rate of 0.6% in other Gypsy populations and a rate of 0.0% among non-Gypsy Europeans (Varon et al. 2003).

The CTDP1 founder mutation (c.863+389C>T) carrier frequency is reported to be 6.9%, 0.6% and 0.0% among the Rudari, other Gypsy populations and non-Gypsy Europeans, respectively (Varon et al. 2003). In another study with 10 CCFDN affected children, all the affected individuals were homozygous for the CTDP1 founder mutation, which was not found in the 116 DNA control samples (Lassuthova et al. 2014).

This test provides full coverage of all coding exons of the CTDP1 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).