ClinVar

In 2 affected brothers from a Sardinian family with Filippi syndrome (FLPIS; 272440), originally described by Battaglia et al. (2008), Hussain et al. (2014) identified homozygosity for a 1-bp duplication (c.571dupA) in exon 4 of the CKAP2L gene, causing a frameshift predicted to result in a premature termination codon (Ile191ASnfsTer6). The unaffected parents were heterozygous for the mutation, which was not found in more than 1,600 exomes from an in-house database or in the dbSNP, 1000 Genomes Project, or Exome Variant Server databases. Functional analysis in patient lymphoblastoid cell lines (LCLs) demonstrated that in contrast to wildtype CKAP2L, the 571dupA mutant was absent from microtubules at the spindle pole in dividing cells in metaphase and telophase. Confocal microscopy of LCLs revealed severe cellular defects, including disorganized mitotic spindles that appeared to be shorter than normal, a long chromatin bridge between daughter nuclei, and supernumerary centrosomes. These abnormalities, present in 25 to 30% of mutant cells, were only seen in 5 to 6% of wildtype cells.