新发突变(de novo mutation, DNM)是导致散发耳聋的重要遗传因素，也是复杂耳聋综合征发病的重要致病原因。为了分析散发耳聋DNM遗传学特征及其致病因素，本文以2015年10月~2023年10月纳入“中国聋病基因组计划”的410个散发耳聋核心家系为对象，对收集到的先证者及其父母的临床信息进行了回顾性分析，同时通过靶向捕获高通量测序、线粒体基因组及全基因组拷贝数变异检测，进行了“父+母+先证者”核心家系遗传学比对分析，应用同源等位基因检测方法来计算DNM先证者核心家系成员之间关系系数。结果发现，这些散发耳聋核心家系中有7.3%(30例)先证者携带17种常染色体显性基因新发SNV、Indel和1种新发拷贝数变异，涵盖所有DNM类型，其中WFS1c.2051C>T、ATP1A3 c.2452G>A、ACTG1 c.94C>T是散发耳聋中常见DNM，基因型C>T变异占比最高(34.6%)；临床特征分析也显示有56.7%(17/30)先证者为非综合征性耳聋，但其中有半数以上(52.9%，9/17)携带明确与“综合征性耳聋”相关的致病基因型，可能存在暂时性“拟”非综合征性耳聋表型特征。本组30例先证者父母的平均生育年龄分别为29.4岁和28.3岁，其中父亲或母亲生育年龄≥35岁的各占13.3%；同时在遗传咨询的先证者家庭结构中，63.3%为独生子女家庭且有明确再生育意愿，16.7%先证者父母为孕育“二孩”产前遗传咨询。遗传咨询时，需要以“父+母+先证者”核心家系为单位进行检测，以便分析DNM在聋病发生中的遗传贡献度；由于DNM发生与父母生育年龄的增加存在一定相关性，因此对于已生育DNM散发耳聋患者家庭，还需要采集听力健康父母的生育年龄及孕产史等临床信息，当这些家庭再生育时建议受孕后进行已明确DNM致病变异的产前诊断并重视妊娠结局。

De novo mutations (DNMs) are significant genetic factors contributing to sporadic hearing loss (HL) and complex HL syndromes. To analyze the genetic counseling characteristics and interpretation of pathogenic DNMs for sporadic HL, we retrospectively analyze the clinical information of probands and their parents from 410 sporadic HL core pedigrees enrolled in the “Chinese Deafness Genome Project (CDGP)” between October 2015 and October 2023. We apply family trio-based genome sequencing (targeted gene capture and high throughput sequencing, mitochondrial genome sequencing, and copy number variants analysis) and validate the samples of their unaffected-parents. Homologous allele sequencing is used to identity by descent (IBD) in the DNM family trios. The results reveal that 7.3% (30 cases) of the probands in these sporadic hearing loss core pedigrees carry 17 types of autosomal dominant gene de novo single nucleotide variants (SNVs), insertions/deletions (Indels), and one type of de novo copy number variation, encompassing all types of DNM. Among them, WFS1 c.2051C>T, ATP1A3 c.2452G>A, and ACTG1 c.94C>T are common DNM in sporadic HL. The genotype C>T transversion exhibit a high number (34.6%). Clinical feature analyses also show that 56.7% (17/30) of the probands have non-syndromic HL, but more than half of them (52.9%, 9/17) carry pathogenic genotypes clearly associated with “syndromic HL”, possibly exhibiting temporary "mimic" non-syndromic HL phenotypic characteristics. The average parental ages at childbirth for the 30 probands are 29.4 years for fathers and 28.3 years for mothers, with 13.3% of fathers or mothers aged ≥35 years. Additionally, among the family structure of the proband of genetic counseling, 63.3% are single-child families with a clear desire for another child, and 16.7% of the probands’ parents seek prenatal genetic counseling for conceiving a “second child”. During genetic counseling, it is essential to test the “family proband-parents’ trios” core pedigree as a unit to analyze the genetic contribution of DNMs to HL. Furthermore, there is a certain correlation between the occurrence of DNMs and increasing parental age at childbirth. Therefore, for families with a history of DNM-associated sporadic HL, it is necessary to collect clinical information such as the parental age at childbirth and obstetric history of hearing-healthy parents. For these families planning another child, it is recommended to undergo prenatal diagnosis for the identified DNM pathogenic variations after conception and pay attention to the pregnancy outcome.