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

Nathan, VaishnaviQIMR Berghofer Medical Research Institute,University of Queensland (author)

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.

Johansson, Peter A.QIMR Berghofer Medical Research Institute (author)
Palmer, Jane M.QIMR Berghofer Medical Research Institute (author)
Howlie, MadeleineQIMR Berghofer Medical Research Institute (author)
Hamilton, Hayley R.QIMR Berghofer Medical Research Institute (author)
Wadt, KarinCopenhagen University Hospital (author)
Jönsson, GöranLund University,Lunds universitet,Lunds Melanomstudiegrupp,Forskargrupper vid Lunds universitet,Melanoma Genomics,Lund Melanoma Study Group,Lund University Research Groups(Swepub:lu)onk-gjo (author)
Brooks, Kelly M.QIMR Berghofer Medical Research Institute (author)
Pritchard, Antonia L.QIMR Berghofer Medical Research Institute,University of the Highlands and Islands (author)
Hayward, Nicholas K.QIMR Berghofer Medical Research Institute (author)
QIMR Berghofer Medical Research InstituteUniversity of Queensland (creator_code:org_t)

By the author/editor: Nathan, Vaishnav ...; Johansson, Peter ...; Palmer, Jane M.; Howlie, Madelein ...; Hamilton, Hayley ...; Wadt, Karin; show more...; Jönsson, Göran; Brooks, Kelly M.; Pritchard, Anton ...; Hayward, Nichola ...; show less...

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Cancer and Oncol ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Medical Genetics

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