The inheritance of predisposition to nonsyndromic familial nonmedullary thyroid cancer (FNMTC) remains unclear. Here, we report six individuals with papillary thyroid cancer (PTC) in two unrelated nonsyndromic FNMTC families. Whole-exome sequencing revealed two germ-line loss-of-function variants occurring within a 28-bp fragment of WDR77, which encodes a core member of a transmethylase complex formed with the protein arginine methyltransferase PRMT5 that is responsible for histone H4 arginine 3 dimethylation (H4R3me2) in frogs and mammals. To date, the association of WDR77 with susceptibility to cancer in humans is unknown. A very rare heterozygous missense mutation (R198H) in WDR77 exon 6 was identified in one family of three affected siblings. A heterozygous splice-site mutation (c.619+1G > C) at the 5′ end of intron 6 is present in three affected members from another family. The R198H variant impairs the interaction of WDR77 with PRMT5, and the splice-site mutation causes exon 6 skipping and results in a marked decrease in mutant messenger RNA, accompanied by obviously reduced H4R3me2 levels in mutation carriers. Knockdown of WDR77 results in increased growth of thyroid cancer cells. Whole-transcriptome analysis of WDR77 mutant patient-derived thyroid tissue showed changes in pathways enriched in the processes of cell cycle promotion and apoptosis inhibition. In summary, we report WDR77 mutations predisposing patients to nonsyndromic familial PTC and link germ-line WDR77 variants to human malignant disease.

非综合征家族性非髓样甲状腺癌 (FNMTC) 易感性的遗传仍不清楚。在这里，我们报告了两个无关的非综合征 FNMTC 家族中的 6 名甲状腺乳头状癌 (PTC) 患者。全外显子组测序揭示了在WDR77的 28 bp 片段内发生的两个种系功能丧失变异体，该片段编码与蛋白质精氨酸甲基转移酶 PRMT5 形成的转甲基酶复合物的核心成员，该酶负责组蛋白 H4 精氨酸 3 甲基化(H4R3me2) 在青蛙和哺乳动物中。迄今为止，WDR77与人类癌症易感性的关联尚不清楚。WDR77中非常罕见的杂合错义突变（R198H ）在一个由三个受影响的兄弟姐妹组成的家庭中发现了外显子 6。内含子 6 5' 末端的杂合剪接位点突变 (c.619+1G > C) 存在于来自另一个家族的三个受影响成员中。R198H变体削弱了WDR77与PRMT5的相互作用，剪接位点突变导致外显子6跳跃，导致突变信使RNA显着减少，同时突变携带者中H4R3me2水平明显降低。WDR77的敲低导致甲状腺癌细胞的生长增加。WDR77突变患者来源的甲状腺组织的全转录组分析显示，在细胞周期促进和细胞凋亡抑制过程中富集的途径发生了变化。总之，我们报告WDR77突变使患者易患非综合征家族性PTC，并将种系WDR77变异与人类恶性疾病联系起来。