Identification of a large rearrangement in CYLD as a cause of familial cylindromatosis

Abstract

Pathogenic mutations in CYLD can be identified in patients affected with Brooke-Spiegler syndrome, (Familial) Cylindromatosis or multiple familial trichoepithelioma. To date, only technologies which are able to identify small point mutations in CYLD, such as sequence and WAVE analysis, were used. Here we describe the identification of a larger rearrangement identified by Quantitative PCR analysis of CYLD, indicating that a combination of these technologies is necessary when searching for pathogenic mutations in CYLD.

Phenotype–genotype correlations for clinical variants caused by CYLD mutations

“…The distribution of nonsense mutations is also unequal in the CYLD gene (Figure 3). One third of the nonsense mutations occur within the region spanning exons 9-11 [Sima et al, 2010;Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Kazakov et al, 2009;Almeida et al, 2008], while the majority (72%) are located within the region spanning exons 12-20 [Sima et al, 2010;Bignell et al, 2000;Zhang et al, 2004;Young et al, 2006;Oranje et al, 2008;Bowen et al, 2005;Grossmann et al, 2013;Oiso et al, 2004;Kazakov et al, 2009;Nagy et al, 2013;Nagy et al, 2012;Zheng et al, 2004;Chen et al, 2011;Almeida et al, 2008]. This latter region does not seem to contain a further mutational hotspot.…”

“…It is of interest to note that 25% of the identified nonsense mutations 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 9 affect glutamine amino acid residues within the CYLD protein, replacing them with stop codons [Sima et al, 2010;Bignell et al, 2000;Grossmann et al, 2013;Zheng et al, 2004;Chen et al, 2011;Almeida et al, 2008]. Nearly half of the nonsense mutations (40%) are recurrent [Sima et al, 2010;Bignell et al, 2000;Oranje et al, 2008;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;…”

“…Nearly half of the nonsense mutations (40%) are recurrent [Sima et al, 2010;Bignell et al, 2000;Oranje et al, 2008;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013;Zheng et al, 2004;Chen et al, 2011]. In general, nonsense mutations -even the same mutation in different individuals -lead to the development of the different clinical variants; thus, nonsense mutations have been associated with the highest phenotypic diversity (Figure 4) [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013].…”

“…BSS, FC and MFT1 were originally described as distinct clinical entities, but due to their overlapping clinical symptoms and their manifestation within the same families, they are now considered as a clinical variants that represent a phenotypic spectrum of a single entity Welch et al, 1968;Young et al, 2006;Oranje et al, 2008]. [Bignell et al, 2000;Bowen et al, 2005;Grossmann et al, 2013;Linos et al, 2011;Lv et al, 2008;Kacerovska et al, 2013;Saggar et al, 2008;Van den Ouweland et al, 2011;Oiso et al, 2004;Zhang et al, 2006;Kazakov et al, 2009;Kazakov et al, 2011;Nagy et al, 2013]. Therefore, it has been hypothesized that BSS, FC and MFT1 are not different disease entities, but represent a phenotypic spectrum of the same disease.…”

Germline mutation analysis in the CYLD gene in Chinese patients with multiple trichoepitheliomas

“…Gross rearrangements and chromosomal deletions are also potential factors. van den Ouweland et al (2011) identified a gross chromosomal rearrangement spanning approximately 5 kb involving the CYLD gene in a patient with familial cylindromatosis. Somatic mutation may also be important.…”