Hereditary Trichilemmal Cysts are Caused by Two Hits to the Same Copy of the Phospholipase C Delta 1 Gene (PLCD1)

Abstract

The autosomal dominant presentation of trichilemmal cysts is one of the most common single gene familial diseases in humans. However, the genetic basis for the inheritance and genesis of these lesions has remained unknown. We first studied patients with multiple trichilemmal cysts using exome and Sanger sequencing. Remarkably, 21 of 21 trichilemmal cysts from 16 subjects all harbored a somatic p.S745L (c.2234 G > A) mutation in phospholipase C delta 1 (PLCD1), a proposed tumor suppressor gene. In addition to this specific somatic mutation in their tumors, 16 of the 17 subjects with multiple trichilemmal cysts were also heterozygous for a p.S460L (c.1379 G > A) germline variant in PLCD1 which is normally present in only about 6% of this population. The one patient of 17 that did not show the p.S460L germline variant had a germline p.E455K (c.1363 C > T) mutation in the same exon of PLCD1. Among 15 additional subjects, with a history suggesting a single sporadic trichilemmal cyst, six were likely familial due to the presence of the p.S460L germline variant. Of the remaining truly sporadic trichilemmal cysts that could be sequenced, only half showed the p.S745L somatic mutation in contrast to 100% of the familial cysts. Surprisingly, in contrast to Knudsen's two hit hypothesis, the p.S745L somatic mutation was always on the same chromosome as the p.S460L germline variant. Our results indicate that familial trichilemmal cysts is an autosomal dominant tumor syndrome resulting from two hits to the same allele of PLCD1 tumor suppressor gene. The c.1379 G > A base change and neighboring bases are consistent with a mutation caused by ultraviolet radiation. Our findings also indicate that approximately one-third of apparently sporadic trichilemmal cysts are actually familial with incomplete penetrance. Sequencing data suggests that the remaining, apparently sporadic, trichilemmal cysts are genetically distinct from familial cysts due to a lack of the germline mutations that underlie familial cysts and a decreased prevalence of the p.S745L somatic mutation relative to familial trichilemmal cysts.

Phospholipase C families: Common themes and versatility in physiology and pathology

“…(Trichilemmal cysts are benign tumours that mostly occur on the scalp.) When this "high risk allele" is further mutated in the C2 domain (S745L), cyst formation on the scalp occurs [331,332]. Analysis of the PLCδ1 activity of the "high risk allele" indicates no impact but when combined with the cyst-specific mutation, activity is dramatically reduced.…”

Scalp trichilemmal cyst: A case report

“…TC lesions are often multiple, and there are a few single lesions. [5][6][7] The lesions are located in the parts with dense hair follicles and vigorous hair growth. More than 90% of them are found in the scalp, and a few are located in vulva and bulbar conjunctiva.…”

A rare ossifying trichilemmal cyst in a young female patient: Case report and literature review

“…TCs can be presented either sporadically or in an autosomal dominant pattern of inheritance, with incomplete penetrance [3,4]. In case of heredity, there are multiple cysts all over the body that appear in young age, and PLCD1 has been recognized as the responsible gene [3,4]. Furthermore, TCs are externally smooth and mobile [1].…”