Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant.
Variable expressivity in a four-generation ACDMPV family with a non-coding hypermorphic SNV in trans to the frameshifting FOXF1 variant.
复制标题
四代 ACDMPV 家族的可变表达性，具有反式移码 FOXF1 变体的非编码超态 SNV。
DOI：
10.1038/s41431-022-01159-x
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Stankiewicz,Paweł
中科院分区：
文献类型：
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作者：
YıldızBölükbaşı,Esra;Karolak,JustynaA;Szafranski,Przemyslaw;Gambin,Tomasz;Matsika,Admire;McManus,Sam;Scott,HamishS;Arts,Peer;Ha,Thuong;Barnett,ChristopherP;Rodgers,Jonathan;Stankiewicz,Paweł
染色体16q24上涉及FOXF1或其远端肺特异增强子的杂合单核苷酸变异(SNV)或拷贝数变异缺失。1在80-90%的肺泡毛细血管发育不良伴肺静脉错位(ACDMPV)患者中被发现，ACDMPV是一种致命的新生儿肺发育障碍。我们描述了一个四代家庭，一个ACDMPV新生儿死亡，她的兄弟姐妹选择性终止妊娠，健康的母亲有肺动脉高压(PAH)病史，一个未受影响的阿姨，一个阿姨因ACDMPV的发现而去世，以及一个据称未受影响的祖母，所有这些都带有FOXF1中的移码变体c.881_902dup(p.Gly302Pros*46)，以及一个已故的有PAH病史的曾祖母。先证者未受影响的母亲的基因组测序分析显示，在肺特异的远端FOXF1增强子中存在一个非编码的推测的调节性SNV rs560517434-A，反式为FOXF1移码突变。用体外荧光素酶报告试验对该变异体进行的功能测试表明，它将FOXF1启动子的活性提高了10倍。我们的研究进一步证明，FOXF1增强子区域的非编码SNV可以挽救致死的ACDMPV表型，并支持复合遗传基因剂量模型。
Heterozygous single nucleotide variants (SNVs) or copy-number variant deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24. 1 have been identified in 80–90% of patients with Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV), a lethal neonatal lung developmental disorder. We describe a four-generation family with a deceased ACDMPV neonate, her sibling from the electively terminated pregnancy, healthy mother with a history of pulmonary arterial hypertension (PAH), an unaffected aunt, an aunt deceased due to findings consistent with ACDMPV, and a reportedly unaffected grandmother, all with the frameshifting variant c. 881_902dup (p. Gly302Profs* 46) in FOXF1, and a deceased great-grandmother with a history of PAH. Genome sequencing analyses in the proband’s unaffected mother revealed a non-coding putative regulatory SNV rs560517434-A within the lung-specific distant FOXF1 enhancer in trans to the FOXF1 frameshift mutation. Functional testing of this variant using an in vitro luciferase reporter assay showed that it increased FOXF1 promoter activity 10-fold. Our studies further demonstrate that non-coding SNVs in the FOXF1 enhancer region can rescue the lethal ACDMPV phenotype and support the compound inheritance gene dosage model.