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Abstract：
OBJECTIVE: To investigate the relation between mutations in ciliopathy-related SPAG6 and RSPH3 and male infertility with severe asthenoteratospermia characterized by multiple flagellar malformations and reveal the intracytoplasmic sperm injection (ICSI) outcomes of those primary ciliary dyskinesia (PCD) patients.
METHODS: Whole-exome sequencing was applied to identify the pathogenic genes for the five PCD patients. The ICSI outcomes of those patients were compared with eight DNAH1-mutated patients and 215 oligo-asthenospermia (OAT) patients.
RESULTS: We identified, for the first time, the compound heterozygous SPAG6 mutations (c.143_145del: p.48_49del, c.585delA: p.Lys196Serfs*6) in a sporadic PCD patient. Further, a novel homozygous nonsynonymous RSPH3 mutation (c.C799T: p.Arg267Cys) was identified in another PCD patient with consanguineous parents. The pathogenicity of these mutations in the assembly of sperm flagella was confirmed by flagellar ultrastructure analysis, immunofluorescence, and quantitative real-time PCR. All five patients underwent six ICSI cycles. The fertilization rate, blastocyst development rate, and clinical pregnancy rate were 69.3%, 50.0%, and 66.7%, respectively. Four of the five couples, including the subjects carrying mutations in SPAG6 or RSPH3, got healthy children born after ICSI. Additionally, the ICSI outcomes of the five PCD couples were statistically comparable with those of the eight DNAH1-mutated couples and the 215 OAT couples.
CONCLUSIONS: Mutations in ciliopathy-related SPAG6 and RSPH3 cause severe asthenoteratospermia characterized by multiple flagellar malformations, resulting in sterility. ICSI is an optimal management with a positive pregnancy outcome.
METHODS: Whole-exome sequencing was applied to identify the pathogenic genes for the five PCD patients. The ICSI outcomes of those patients were compared with eight DNAH1-mutated patients and 215 oligo-asthenospermia (OAT) patients.
RESULTS: We identified, for the first time, the compound heterozygous SPAG6 mutations (c.143_145del: p.48_49del, c.585delA: p.Lys196Serfs*6) in a sporadic PCD patient. Further, a novel homozygous nonsynonymous RSPH3 mutation (c.C799T: p.Arg267Cys) was identified in another PCD patient with consanguineous parents. The pathogenicity of these mutations in the assembly of sperm flagella was confirmed by flagellar ultrastructure analysis, immunofluorescence, and quantitative real-time PCR. All five patients underwent six ICSI cycles. The fertilization rate, blastocyst development rate, and clinical pregnancy rate were 69.3%, 50.0%, and 66.7%, respectively. Four of the five couples, including the subjects carrying mutations in SPAG6 or RSPH3, got healthy children born after ICSI. Additionally, the ICSI outcomes of the five PCD couples were statistically comparable with those of the eight DNAH1-mutated couples and the 215 OAT couples.
CONCLUSIONS: Mutations in ciliopathy-related SPAG6 and RSPH3 cause severe asthenoteratospermia characterized by multiple flagellar malformations, resulting in sterility. ICSI is an optimal management with a positive pregnancy outcome.
摘要：
目的：探讨纤毛病变相关的SPAG6和RSPH3基因突变与男性不育合并以多个鞭毛畸形为特征的重度弱精子症的关系，揭示原发性纤毛运动障碍（PCD）患者的胞浆内单精子注射（ICSI）结果。
方法：采用全外显子组测序法鉴定5例PCD患者的致病基因。将这些患者的ICSI结果与8名DNAH1突变患者和215名少弱精子症（OAT）患者进行了比较。
结果：我们确定，第一次,复合杂合SPAG6突变(c.143_145del：p.48_49del，c.585delA：p.Lys196Serfs*6）在散发性PCD患者中。Further,一种新的纯合非同义RSPH3突变（c。C799T：p.Arg267Cys）在另一名具有近亲父母的PCD患者中鉴定。通过鞭毛超微结构分析证实了这些突变在精子鞭毛组装中的致病性，免疫荧光，和定量实时PCR。所有5例患者均接受6个ICSI周期。受精率,囊胚发育率，临床妊娠率为69.3%,50.0%,和66.7%，分别。五对夫妇中的四对,包括携带SPAG6或RSPH3突变的受试者，在ICSI后出生的健康儿童。此外,5对PCD夫妇的ICSI结局与8对DNAH1突变夫妇和215对OAT夫妇的ICSI结局具有统计学可比性.
结论：纤毛病相关SPAG6和RSPH3的突变可导致以多个鞭毛畸形为特征的严重弱精子症，导致不育。ICSI是一种具有积极妊娠结局的最佳管理方法。
方法：采用全外显子组测序法鉴定5例PCD患者的致病基因。将这些患者的ICSI结果与8名DNAH1突变患者和215名少弱精子症（OAT）患者进行了比较。
结果：我们确定，第一次,复合杂合SPAG6突变(c.143_145del：p.48_49del，c.585delA：p.Lys196Serfs*6）在散发性PCD患者中。Further,一种新的纯合非同义RSPH3突变（c。C799T：p.Arg267Cys）在另一名具有近亲父母的PCD患者中鉴定。通过鞭毛超微结构分析证实了这些突变在精子鞭毛组装中的致病性，免疫荧光，和定量实时PCR。所有5例患者均接受6个ICSI周期。受精率,囊胚发育率，临床妊娠率为69.3%,50.0%,和66.7%，分别。五对夫妇中的四对,包括携带SPAG6或RSPH3突变的受试者，在ICSI后出生的健康儿童。此外,5对PCD夫妇的ICSI结局与8对DNAH1突变夫妇和215对OAT夫妇的ICSI结局具有统计学可比性.
结论：纤毛病相关SPAG6和RSPH3的突变可导致以多个鞭毛畸形为特征的严重弱精子症，导致不育。ICSI是一种具有积极妊娠结局的最佳管理方法。
