Premium
Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma
Author(s) -
Nathan Vaishnavi,
Johansson Peter A.,
Palmer Jane M.,
Howlie Madeleine,
Hamilton Hayley R.,
Wadt Karin,
Jönsson Göran,
Brooks Kelly M.,
Pritchard Antonia L.,
Hayward Nicholas K.
Publication year - 2019
Publication title -
pigment cell and melanoma research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.618
H-Index - 105
eISSN - 1755-148X
pISSN - 1755-1471
DOI - 10.1111/pcmr.12804
Subject(s) - genetics , sanger sequencing , biology , oculocutaneous albinism , germline , missense mutation , frameshift mutation , gene , genetic predisposition , compound heterozygosity , allele , exon , mutation
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.