Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma
Germline variants in oculocutaneous albinism genes and predisposition to familial cutaneous melanoma
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DOI：
10.1111/pcmr.12804
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发表时间：
2019-11-01
影响因子：
4.3
通讯作者：
Hayward, Nicholas K.
中科院分区：
文献类型：
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作者：
Nathan, Vaishnavi;Johansson, Peter A.;Hayward, Nicholas K.
大约1%-2%的皮肤黑色素瘤（CM）被归类为强家族性。我们试图利用受影响个体的下一代测序来研究已知易感基因阴性家庭中不明原因的CM易感性。通过Sanger测序评估家族内感兴趣的种系变异的分离。我们的CM队列中存在几种皮肤白化病（OCA）基因的杂合变异：TYR， OCA2， TYRP1和SLC45A2。OCA是一组常染色体隐性遗传疾病，导致眼睛、头发和皮肤色素沉着缺陷。被归类为OCA致病性的错义变异存在于多个家族中，其中一些与CM完全分离。功能受损的TYR p.T373K变体存在于三个不相关的家族中。在OCA2中，已知的致病变异：p.V443I和p.N489D分别存在于三个家族和一个家族中。我们发现了一个可能致病的SLC45A2移码变异，在一个四人家庭中与CM完全分离。另一个四例家族在TYRP1中含有不确定功能意义的共分离变异体（p.A24T和p.R153C）。我们的结论是，罕见的，杂合变异的OCA基因赋予CM的中等风险。
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.