Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing
Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing
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DOI：
10.1177/0022034516678829
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发表时间：
2017-02-01
影响因子：
7.6
通讯作者：
Carels, C. E. L.
中科院分区：
文献类型：
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作者：
Khandelwal, K. D.;Ishorst, N.;Carels, C. E. L.
干扰素调节因子6（IRF 6）的常见变异与非综合征性唇腭裂（NSCL/P）以及牙齿发育不全（TA）有关。这些变异对2种先天性疾病的风险很小，只能解释一小部分遗传性。另一方面，已知许多IRF 6突变是综合征性口面裂（OFC）疾病的单基因原因。我们假设IRF 6突变在某些罕见的情况下也可能导致非综合征型OFC。为了发现IRF 6中负责非综合征型OFC和TA的新的罕见变异，我们使用分子倒置探针（MIP）对1，072名OFC患者，67名TA患者和706名对照进行了靶向多重测序。我们在OFC患者中发现了3种潜在致病性的从头突变。此外，还发现了3种罕见的错义变体，无法明确显示其致病性，因为所有变体均遗传自未受影响的亲本或亲本DNA不可用。对这些变异患者的回顾性研究显示，其中一名患者的唇凹具有提示货车德沃德综合征（VWS）表型的新生突变，而在其他患者中，未发现唇凹。
Common variants in interferon regulatory factor 6 (IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.