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Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma

Nathan, Vaishnavi ; Johansson, Peter A. ; Palmer, Jane M. ; Howlie, Madeleine ; Hamilton, Hayley R. ; Wadt, Karin ; Jönsson, Göran LU ; Brooks, Kelly M. ; Pritchard, Antonia L. and Hayward, Nicholas K. (2019) In Pigment Cell and Melanoma Research 32(6). p.854-863
Abstract

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next-generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised... (More)

Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next-generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four-case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cutaneous melanoma, family genetics, OCA, OCA2, oculocutaneous albinism, pigmentation, SLC45A2, TYR, TYRP1
in
Pigment Cell and Melanoma Research
volume
32
issue
6
pages
854 - 863
publisher
Wiley-Blackwell
external identifiers
  • scopus:85068449107
  • pmid:31233279
ISSN
1755-1471
DOI
10.1111/pcmr.12804
language
English
LU publication?
yes
id
6757d02b-6b10-4b78-a711-953560d84b11
date added to LUP
2019-07-19 10:37:20
date last changed
2024-06-11 22:01:40
@article{6757d02b-6b10-4b78-a711-953560d84b11,
  abstract     = {{<p>Approximately 1%–2% of cutaneous melanoma (CM) is classified as strongly familial. We sought to investigate unexplained CM predisposition in families negative for the known susceptibility genes using next-generation sequencing of affected individuals. Segregation of germline variants of interest within families was assessed by Sanger sequencing. Several heterozygous variants in oculocutaneous albinism (OCA) genes: TYR, OCA2, TYRP1 and SLC45A2, were present in our CM cohort. OCA is a group of autosomal recessive genetic disorders, resulting in pigmentation defects of the eyes, hair and skin. Missense variants classified as pathogenic for OCA were present in multiple families and some fully segregated with CM. The functionally compromised TYR p.T373K variant was present in three unrelated families. In OCA2, known pathogenic variants: p.V443I and p.N489D, were present in three families and one family, respectively. We identified a likely pathogenic SLC45A2 frameshift variant that fully segregated with CM in a family of four cases. Another four-case family harboured cosegregating variants (p.A24T and p.R153C) of uncertain functional significance in TYRP1. We conclude that rare, heterozygous variants in OCA genes confer moderate risk for CM.</p>}},
  author       = {{Nathan, Vaishnavi and Johansson, Peter A. and Palmer, Jane M. and Howlie, Madeleine and Hamilton, Hayley R. and Wadt, Karin and Jönsson, Göran and Brooks, Kelly M. and Pritchard, Antonia L. and Hayward, Nicholas K.}},
  issn         = {{1755-1471}},
  keywords     = {{cutaneous melanoma; family genetics; OCA; OCA2; oculocutaneous albinism; pigmentation; SLC45A2; TYR; TYRP1}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{6}},
  pages        = {{854--863}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Pigment Cell and Melanoma Research}},
  title        = {{Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma}},
  url          = {{http://dx.doi.org/10.1111/pcmr.12804}},
  doi          = {{10.1111/pcmr.12804}},
  volume       = {{32}},
  year         = {{2019}},
}