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Abstract：
Germline mosaicisms could be inherited to offspring, which considered as \"de novo\" in most cases. Paternal germline MECP2 mosaicism has been reported in fathers of girls with Rett syndrome (RTT) previously. For further study, we focused on MECP2 germline mosaicism in males, not only RTT fathers.
Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms.
Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms.
Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as \"de novo\", more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.
Thirty-two fathers of RTT girls with MECP2 pathogenic mutations and twenty-five healthy adult males without history and family history of RTT or other genetic disorders were recruited. Sperm samples were collected and ten MECP2 hotspot mutations were detected by micro-droplet digital PCR (mDDPCR). And routine semen test was performed at the same time if the sample was sufficient. Additionally, blood samples were also detected for those with sperm MECP2 mosaicisms.
Nine fathers with RTT daughters (28.1%, 9/32) were found to have MECP2 mosaicism in their sperm samples, with the mutant allele fractions (MAFs) ranging from 0.05% to 7.55%. Only one father with MECP2 c.806delG germline mosaicism (MAF 7.55%) was found to have mosaicism in the blood sample, with the MAF was 0.28%. In the group of healthy adult males, MECP2 mosaicism was found in 7 sperm samples (28.0%, 7/25), with the MAFs ranging from 0.05% to 0.18%. None of the healthy adult males with MECP2 germline mosaicisms were found with MECP2 mosaicism in blood samples. There were no statistical differences in age, or the incidence of asthenospermia between fathers with RTT daughters and healthy adult males with MECP2 germline mosaicisms. Additionally, there was no linear correlation between MAFs of MECP2 mosaicisms and the age of males with germline MECP2 mosaicisms.
Germline MECP2 mosaicism could be found not only in fathers with RTT daughters but also in healthy adult males without family history of RTT. As germline mosaic mutations may be passed on to offspring which commonly known as \"de novo\", more attention should be paid to germline mosaicism, especially in families with a proband diagnosed with genetic disorders.
摘要：
背景：生殖系镶嵌可以遗传给后代，在大多数情况下，这被认为是“从头”。先前已在患有Rett综合征（RTT）的女孩的父亲中报道了父亲种系MECP2镶嵌。为了进一步研究，我们专注于男性的MECP2种系镶嵌，不仅仅是RTT的父亲。
方法：招募32名患有MECP2致病突变的RTT女孩父亲和25名没有RTT或其他遗传性疾病病史和家族史的健康成年男性。收集精子样品,通过微滴数字PCR(mDDPCR)检测10个MECP2热点突变。如果样品足够，则同时进行常规精液测试。此外,还检测了精子MECP2镶嵌的血液样本.
结果：9个有RTT女儿的父亲（28.1%，9/32）被发现在他们的精子样本中具有MECP2镶嵌性，突变等位基因分数（MAFs）范围为0.05％至7.55％。只有一位患有MECP2c.806delG种系镶嵌性（MAF7.55％）的父亲在血液样本中发现镶嵌性，MAF为0.28%。在健康成年男性群体中，在7个精子样本中发现了MECP2镶嵌（28.0％，7/25),MAFs范围从0.05%到0.18%。在血液样本中没有发现MECP2种系镶嵌的健康成年男性。年龄差异无统计学意义,或患有RTT女儿的父亲与患有MECP2生殖系镶嵌的健康成年男性之间的弱精子症的发生率。此外,MECP2镶嵌的MAFs与MECP2镶嵌的男性年龄之间没有线性相关性。
结论：不仅在有RTT女儿的父亲中，而且在没有RTT家族史的健康成年男性中也可以发现胚系MECP2镶嵌。由于种系马赛克突变可能会传递给后代，通常称为“从头”，应该更加注意种系镶嵌，尤其是在先证者被诊断为遗传性疾病的家庭中。
方法：招募32名患有MECP2致病突变的RTT女孩父亲和25名没有RTT或其他遗传性疾病病史和家族史的健康成年男性。收集精子样品,通过微滴数字PCR(mDDPCR)检测10个MECP2热点突变。如果样品足够，则同时进行常规精液测试。此外,还检测了精子MECP2镶嵌的血液样本.
结果：9个有RTT女儿的父亲（28.1%，9/32）被发现在他们的精子样本中具有MECP2镶嵌性，突变等位基因分数（MAFs）范围为0.05％至7.55％。只有一位患有MECP2c.806delG种系镶嵌性（MAF7.55％）的父亲在血液样本中发现镶嵌性，MAF为0.28%。在健康成年男性群体中，在7个精子样本中发现了MECP2镶嵌（28.0％，7/25),MAFs范围从0.05%到0.18%。在血液样本中没有发现MECP2种系镶嵌的健康成年男性。年龄差异无统计学意义,或患有RTT女儿的父亲与患有MECP2生殖系镶嵌的健康成年男性之间的弱精子症的发生率。此外,MECP2镶嵌的MAFs与MECP2镶嵌的男性年龄之间没有线性相关性。
结论：不仅在有RTT女儿的父亲中，而且在没有RTT家族史的健康成年男性中也可以发现胚系MECP2镶嵌。由于种系马赛克突变可能会传递给后代，通常称为“从头”，应该更加注意种系镶嵌，尤其是在先证者被诊断为遗传性疾病的家庭中。
