A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features.
A Newfoundland cohort of familial and sporadic idiopathic pulmonary fibrosis patients: clinical and genetic features.
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DOI：
10.1186/1465-9921-13-64
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发表时间：
2012-08-01
影响因子：
5.8
通讯作者：
Woods MO
中科院分区：
文献类型：
--
作者：
Fernandez BA;Fox G;Bhatia R;Sala E;Noble B;Denic N;Fernandez D;Duguid N;Dohey A;Kamel F;Edwards L;Mahoney K;Stuckless S;Parfrey PS;Woods MO
特发性肺纤维化（IPF）是一种成人发病的特发性间质性肺炎（IIP），通常在50至70岁之间诊断。家族性肺纤维化（FPF）患者至少有一个受影响的一级或二级亲属，占病例的0.5-20%。我们确定并收集了来自加拿大纽芬兰的IPF患者的大规模人群队列的DNA样本。对于每个先证者，记录家族史并审查医疗记录。每个先证者被分为家族性（28例）或散发性（50例），所有78名先证者都被筛选出4个高度外显的成人发病PF基因（SFTPC，SFTPA 2，TERT，TERC）的变异。入组了78例IPF先证者，其中28例（35.9%）有阳性家族史。这28名家族性患者导致招募了另外49名受影响的亲属（共77名FPF患者）。到60岁时，42%的家族性队列被诊断为PF，而散发性患者仅为16%（χ2 = 8.77，p = 0.003）。家族性组的平均诊断年龄显著低于散发性组（61.4岁vs. 66.6岁，p = 0.012），诊断年龄范围更广（19-92岁vs. 47-82岁）。77例FPF患者中有33例（42.8%）有组织诊断，除5例外，所有患者均具有普通间质性肺炎组织学。与其他已发表的病例系列相比，家族性IIP组织学更均匀。28个家族性先证者中有3个（10.7%）和50个散发性先证者中没有一个在检测的4个基因中有致病性变异。所有三个家族先证者都有TERT突变。其他与端粒酶缺陷相关的表型也出现在这些家族中，包括肝硬化、骨髓发育不全和过早变白。对来自两个家庭的突变携带者进行端粒长度测定，并证实端粒相关缺陷。在我们的队列中的家族性病例的比例高于任何以前报道的估计，我们认为，这是由于纽芬兰队列是种族同质的，并从创始人人口。在我们收集的患者中，45岁之前诊断为IPF可预测家族性疾病。在三个TERT突变家族中的两个中，系谱外观与遗传预期一致。在其他25个已知PF基因突变阴性的FPF家族中，我们没有发现其他端粒酶相关的医学问题（骨髓功能障碍，肝硬化），我们假设在我们的人群中有新的PF基因分离。
Idiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases. We ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT,TERC). Seventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19–92 years compared with 47–82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency. The proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population.
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