First evidence of genotype-phenotype correlations in Gorlin syndrome
First evidence of genotype-phenotype correlations in Gorlin syndrome
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DOI：
10.1136/jmedgenet-2017-104669
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Lear, John T.
中科院分区：
文献类型：
--
作者：
Evans, D. Gareth;Oudit, Deemesh;Lear, John T.
背景Gorlin综合征(GS)是一种常染色体显性遗传性综合征，以多发性基底细胞癌(BCC)为特征，颌骨囊肿和儿童早期髓母细胞瘤的风险增加。Ptch1和SuFU中编码Sonic Hedgehog途径组件的杂合生殖系变体解释了大多数情况。方法我们评估了182名符合GS诊断标准的个体的遗传和表型数据(中位年龄：47.1岁；IQR：31.1-61.1)。结果与未发现突变的患者相比，具有杂合性突变的患者更容易被早期诊断(p=0.02)、颌骨囊肿(p=0.002)、肋骨裂(p=0.003)或任何骨骼异常(p=0.003)。具有ptch1错义变异的患者诊断较晚(p=0.03)，并且与其他致病ptch1变异的患者相比，发生至少10个基底细胞癌和颌骨囊肿的可能性较小(p=0.03)。UFU致病变异者发生髓母细胞瘤(p=0.009)、脑膜瘤(p=0.02)或卵巢纤维瘤(p=0.015)的可能性明显高于PTCH1致病变异者，但发生颌骨囊肿的可能性较低(p=0.0004)。结论GS的临床异质性可部分由潜在的或SUFU变异者解释。
Background Gorlin syndrome (GS) is an autosomal dominant syndrome characterised by multiple basal cell carcinomas (BCCs) and an increased risk of jaw cysts and early childhood medulloblastoma. Heterozygous germline variants in PTCH1 and SUFU encoding components of the Sonic hedgehog pathway explain the majority of cases. Here, we aimed to delineate genotype-phenotype correlations in GS.Methods We assessed genetic and phenotypic data for 182 individuals meeting the diagnostic criteria for GS (median age: 47.1; IQR: 31.1-61.1). A total of 126 patients had a heterozygous pathogenic variant, 9 had SUFU pathogenic variants and 46 had no identified mutation.Results Patients with variants were more likely to be diagnosed earlier (p=0.02), have jaw cysts (p=0.002) and have bifid ribs (p=0.003) or any skeletal abnormality (p=0.003) than patients with no identified mutation. Patients with a missense variant in PTCH1 were diagnosed later (p=0.03) and were less likely to develop at least 10 BCCs and jaw cysts than those with other pathogenic PTCH1 variants (p=0.03). Patients with SUFU pathogenic variants were significantly more likely than those with PTCH1 pathogenic variants to develop a medulloblastoma (p=0.009), a meningioma (p=0.02) or an ovarian fibroma (p=0.015), but were less likely to develop a jaw cyst (p=0.0004).Conclusion We propose that the clinical heterogeneity of GS can in part be explained by the underlying or SUFU variant.