Genetic Testing in CYLD Cutaneous Syndrome: An Update

Figures & data

Figure 1 Cylindromas: germline and mosaic presentations. (A) Cylindromas and spiradenomas progressively grow and form a confluent mass, as seen in this severely affected patient with CCS. (B) Mosaic presentations of unilateral cylindromas, that may warrant skin biopsy and genetic testing to determine a recurrently detected pathogenic variant across multiple tumours. Image (B) reprinted from J Am Acad Dermatol, 81, Arefi M, Wilson V, Muthiah S et al. Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission. 1300–1307, Copyright (2019), with permission from Elsevier.²⁴

Figure 2 Skin tumours frequently seen in CCS. (A) Cylindroma. (B) Spiradenoma indicated by black arrow. (C) Trichoepithelioma indicated by white arrows. Reprinted from Dermatol Clin, 35 (1), Dubois A, Hodgson K, Rajan N. Understanding Inherited Cylindromas: Clinical Implications of Gene Discovery. 61–71, Copyright (2017), with permission from Elsevier.¹¹⁶

Figure 3 Pulmonary and cutaneous cylindromas visualised radiologically and endoscopically. (A) Spatial location of cutaneous CCS tumours seen on a CT with contrast indicated in green, and pulmonary CCS tumours indicated in yellow. Adapted from (B) Intra bronchial CCS tumour visualised during bronchoscopy. Adapted with permission from Brown SM, Arefi M, Stones R, et al. Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers. Br J Dermatol. 2018;179:662–668. © 2018 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.⁴¹

Figure 4 CYLD gene pathogenic variants identified to date. (A) Exonic locations of CYLD pathogenic variants in CCS patients; note a predisposition to the 3’ end of the gene, from which the catalytic domains are encoded. (B) Frameshift and nonsense pathogenic variants resulting in a predicted truncating protein are the most frequent mutation type seen.

Table 1 List of Published Pathogenic Variants in CCS

Paper	Year	Mutation	Exon	Mutation Type
Vanecek et al.	2014	c.-34111_*297858del378779	N/A	Large deletion
Nasti et al.	2009	c.561_562dupT	5	NS
Parren et al.	2018	c.588_591dupTGTT	5	FS
Shiver et al.	2015	c.703G>A	5	MS
Parren et al.	2018	c.822delC	6	FS
Vanecek et al.	2014	c.914–6398_1769del13642ins20	N/A	Large deletion
Dubois et al.	2015	c.966dupG	8	FS
Grossman et al.	2013	c.1027dupA	9	FS
Saggar et al.	2008	c.1096_1097del	9	FS
Bignall et al, Bowen et al, Saggar et al.	2000;2005;2008	c.1112C>A	9	NS
Almeida et al.	2008	c.1135G>T	9	NS
Kazakov et al.	2009	c.1139–148A>G	10	Splice
Wu et al.	2014	c.1169_1170delCA	10	FS
Ying et al.	2012	c.1178_1179delCA	10	FS
Almeida et al.	2008	c.1207C>T	10	NS
Liang et al.	2008	c.1364_1365del	10	FS
Nasti et al.	2009	c.1392_1393dupT	10	NS
Bignell et al.	2000	c.1455T>A	10	NS
Zheng et al.	2004	c.1462delA	10	FS
Ly et al.	2004	c.1518+2T>C	10	Splice
Bignell et al.	2000	c.1569T>G	11	NS
Solak et al.	2019	c.1609A>T	11	NS
Andersson et al.	2019	c.1613_1614delGC	11	FS
Saggar et al.	2008	c.1628_1629del	11	NS
Bignell et al.	2000	c.1681_1682del	11	FS
van den Ouweland et al.	2011	c.1682T>A	11	NS
Kazakov et al.	2010	c.1684+1G>A	11	Splice
Bowen et al; Saggar et al.	2005, 2008	c.1755_1758dup	12	FS
Bignell et al.	2000	c.1776delA	12	FS
Pinho et al.	2015	c.1783C>T	12	NS
Zuo et al.	2007	c.1787G>A	12	MS
Nagy et al.	2021	c.1806_1809delCTTA	12	NS
Tantcheva-Poór et al.	2016	c.1821_1826+1delinsCT	12	FS
Huang et al.	2009	c.1826+1G>A	12	Splice
Liang et al.	2005	c.1826+2T>G	12	Splice
Kazakov et al.	2011	c.1826+1G>T	12	Splice
Huang et al.	2009	IVS12+1G>A	12	Splice
Bignell et al, Saggar et al.	2000, 2008	c.1830dupA	13	FS
Reuven et al.	2013	c.1843delT	13	FS
Bignell et al, Saggar et al.	2000, 2008	c.1859_1860del	13	FS
Saggar et al.	2008	c.1863dupA	13	FS
Nasti et al.	2009	c.1893_1906delATATTATAGTGAAA	13	NS
Chen et al.	2011	c.1925delC	13	FS
Bignell et al.	2000	c.1935dupT	13	NS
Nasti et al.	2009	c.1950–2A>T	14	Splice
Nasti et al.	2009	c.1950_1953-1delGATA	14	Splice
Kazakov et al.	2009	c.1961T>A	14	MS
Heinritz et al.	2006	c.2012_2021del	14	FS
Nagy N et al.	2015	c.2032G>T	14	NS
Kacerovska et al.	2013	c.2041+1G>T	15	Splice
Almeida et al.	2008	c.2042A>G	15	MS
Malzone et al.	2015	c.2042–1G>C	15	Splice
van den Ouweland et al.	2011	c.2065_2066delCT	15	FS
van den Ouweland et al.	2011	c.2068_2069delTTinsC	15	FS
Guardoli et al.	2014	c.2070delT	15	FS
Almeida et al, Parren et al.	2008, 2018	c.2081delT	15	NS
Sima et al, Cakmak Genc et al.	2010, 2019	c.2104delA	15	FS
Salhi et al.	2004	c.2104dupA	15	FS
Sima et al.	2010	c.2108+1G>C	15	Splice
Parren et al.	2018	c.2108+1G>A	15	Splice
Parren et al.	2018	c.2109–2A>C	15	Splice
Melly et al.	2012	c.2116_2117insATTAG	16	FS
Sima et al.	2010	c.2119C>T	16	NS
Zheng et al, Chen et al.	2004, 2011	c.2128C>T	16	NS
Bignall et al.	2000	c.2138delA	16	FS
van den Ouweland et al.	2011	c.2146C>A	16	MS
Saggar et al.	2008	c.2154dupT	16	FS
Grossman et al.	2013	c.2155dupA	16	FS
Sima et al.	2010	c.2170_2171insTC	16	FS
Bignall et al, Scheinfeld et al, Saggar et al.	2000, 2003, 2008	c.2172delA	16	FS
Saggar et al.	2008	c.2214delT	16	FS
Hu et al, Saggar et al.	2003, 2008	c.2240A>G	16	MS
Liang et al.	2005	c.2240_2241delA	16	FS
Fujii et al.	2017	c.2242–1G>A	16	Splice
Parren et al.	2018	c.2242–2A>G	16	Splice
Poblete Gutierrez et al.	2002	c.2252delG	17	FS
Hongli et al.	2014	c.2255delT	17	FS
Kazakov et al.	2011	c.2259dupT	17	FS
Parren et al.	2018	c.2261T>G	17	MS
Bignall et al, Oiso et al, Zhang et al, Farkas et al.	2000, 2004, 2006, 2016	c.2272C>T	17	NS
Grossman et al.	2013	c.2288_2289delTT	17	FS
Saggar et al.	2008	c.2290_2294del	17	FS
Grossman et al.	2013	c.2291_2295delAACTA	17	FS
Sima et al.	2010	c.2299A>T	17	NS
Bignell et al.	2000	c.2305_2306insC	17	FS
Bowen et al; Saggar et al.	2005, 2008	c.2305delA	17	FS
Wang et al.	2010	c.2317G>A	17	MS
Hester et al.	2013	c.2330_2331delTA	17	FS
Wang et al.	2010	c.2335G>A	17	MS
Bowen et al, Saggar et al.	2005, 2008	c.2339T>G	17	NS
Bignall et al.	2000	c.2350+5G>A	18	Splice
Zhang et al.	2004	c.2355_2358del	18	FS
Parren et al.	2018	c.2409C>A	18	NS
Liang et al.	2008	c.2409C>G	18	NS
Amaro C et al.	2010	c.2449delT	18	NS
Bignall et al.	2000	c.2460delC	18	NS
Hunstig et al.	2015	c.2465insAACA	18	FS
Bignall et al.	2000	c.2467C>T	18	NS
Bignall et al.	2000	c.2469+1G>A	18	Splice
Parren et al.	2018	c.2540G>A	19	NS
Almeida et al.	2008	c.2546G>A	19	NS
Scholz et al.	2010	c.2552_2553insA	19	FS
Bignall et al.	2000	c.2569C>T	19	NS
Parren	2018	c.2581T>G	19	MS
Bignall et al, Oranje et al.	2000, 2008	c.2602G>T	19	NS
Nagy et al.	2012	c.2613C>G	19	MS
Grossman et al.	2013	c.2641delG	19	FS
Parren et al.	2018	c.2649dupT	19	FS
van den Ouweland et al.	2011	c.2655G>A	19	NS
van den Ouweland et al.	2011	c.2662_2664delTTT	19	Deletion
Tantcheva-Poór et al.	2016	c.2666A>T	19	MS
van den Ouweland et al.	2011	c.2686+60_3340del5632	20	Large deletion
Espana et al.	2007	c.2687G>C	20	MS
Furuichi et al.	2012	c.2709dupT	20	FS
Ly et al.	2008	c.2711C>T	20	MS
Tantcheva-Poór et al.	2016	c.2712delT	20	FS
Grossman et al.	2013	c.2713C>T	20	NS
Sima et al.	2010	c.2729dupC	20	FS
Bignall et al, Bowen et al, Young et al, Saggar et al, Kazakov et al, Nagy et al.	2000, 2005, 2006, 2008, 2009, 2013	c.2806C>T	20	NS
Sima et al.	2010	c.2814_2817delGCTT	20	FS
Qian et al.	2014	c.2815delC	20	FS
Zheng et al.	2004	c.2822A>T	20	MS
Nagy et al.	2021	c.2841C>G	20	NS

Note: All mutations described in relation to reference sequence NM_015247.

Abbreviations: FS, frameshift; NS, nonsense; MS, missense.

Figure 5 A suggested testing strategy for CCS that addresses germline and mosaic presentations. *RNA from blood leucocytes require special collection tubes; **in principle such a patient may still yet harbour a germline pathogenic variant, and it remains the clinician’s decision if she would prefer to pursue GERMLINE testing first.

Abbreviations: PV, pathogenic variant; SNV, single nucleotide variant.

Figure 6 An overview of risk of transmission of germline and mosaic variants in CCS.

Notes: Reprinted from J Am Acad Dermatol, 81, Arefi M, Wilson V, Muthiah S et al. Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission. 1300–1307, Copyright (2019), with permission from Elsevier.²⁴

Arefi M, Wilson V, Muthiah S, et al. Diverse presentations of cutaneous mosaicism occur in CYLD cutaneous syndrome and may result in parent-to-child transmission. J Am Acad Dermatol. 2019;81:1300–1307. doi:10.1016/j.jaad.2019.05.021

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Dubois A, Hodgson K, Rajan N. Understanding inherited cylindromas: clinical implications of gene discovery. Dermatol Clin. 2017;35(1):61–71. doi:10.1016/j.det.2016.08.002

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Brown SM, Arefi M, Stones R, et al. Inherited pulmonary cylindromas: extending the phenotype of CYLD mutation carriers. Br J Dermatol. 2018;179:662–668. doi:10.1111/bjd.16573

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