Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia
Identification of genetic variants in CFAP221 as a cause of primary ciliary dyskinesia
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DOI：
10.1038/s10038-019-0686-1
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发表时间：
2020-02-01
影响因子：
3.5
通讯作者：
Zariwala, Maimoona A.
中科院分区：
文献类型：
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作者：
Bustamante-Marin, Ximena M.;Shapiro, Adam;Zariwala, Maimoona A.
原发性纤毛运动障碍(PCD)是一种罕见的疾病，它会影响活动纤毛的生物发生或功能，从而导致慢性呼吸道疾病。PCD在遗传和表型上是异质性的，在40多个基因中发现了致病突变；然而，许多病例的遗传学基础尚不清楚。通过全外显子测序，我们确定了三个有PCD临床症状但纤毛结构正常的受影响兄弟姐妹，携带CFAP221基因的复合杂合性功能丧失变体。计算分析表明，这些变异是所有三个兄弟姐妹共有的最具破坏性的等位基因。其中一个受试者的鼻上皮细胞的搏动频率略有降低(16.5 Hzvs 17.7 Hzp=0.16)；然而，波形分析显示CFAP221缺陷的纤毛以异常的环状模式跳动。这些结果表明，CFAP221的遗传变异导致PCD，在怀疑PCD但纤毛结构和搏动频率正常的情况下，CFAP221应被视为候选基因。
Primary ciliary dyskinesia (PCD) is a rare disorder that affects the biogenesis or function of motile cilia resulting in chronic airway disease. PCD is genetically and phenotypically heterogeneous, with causative mutations identified in over 40 genes; however, the genetic basis of many cases is unknown. Using whole-exome sequencing, we identified three affected siblings with clinical symptoms of PCD but normal ciliary structure, carrying compound heterozygous loss-of-function variants in CFAP221. Computational analysis suggests that these variants are the most damaging alleles shared by all three siblings. Nasal epithelial cells from one of the subjects demonstrated slightly reduced beat frequency (16.5 Hz vs 17.7 Hz, p = 0.16); however, waveform analysis revealed that the CFAP221 defective cilia beat in an aberrant circular pattern. These results show that genetic variants in CFAP221 cause PCD and that CFAP221 should be considered a candidate gene in cases where PCD is suspected but cilia structure and beat frequency appear normal.