探讨携带者筛查发现的孕妇携带抗肌萎缩蛋白基因(被称为DMD基因)部分重复的致病性。

选择2022年3月至11月在南京市妇幼保健院产前诊断中心接受携带者筛查发现的携带DMD基因部分重复的2例孕妇(孕妇1、2)为研究对象。采用毛细管电泳方法进行携带者筛查，对发现的DMD基因部分重复，采用多重连接探针扩增技术(MLPA)进行验证。对2例孕妇的家系成员采用MLPA检测DMD基因拷贝数变异(CNV)，并绘制携带DMD基因部分重复的家系系谱图。根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》(以下简称为"ACMG指南")，对检出的基因突变进行致病性评级。结合孕妇1、2携带的DMD基因部分重复的数据库收录与文献报道情况，以及家系中男性携带者的临床表现，分析DMD基因部分重复的致病性。本研究经南京市妇幼保健院伦理委员会审核并批准[审批文号：宁妇伦字(2020)KY-057]。这2例孕妇及其家系相关成员对筛查过程均知情同意，并签署临床研究知情同意书。

①携带者筛查结果显示，孕妇1、2分别携带DMD基因第1~6外显子杂合重复和第1~9外显子杂合重复，分别对应染色体位置为ChrX: 33339448-32816399(GRCh38)和ChrX: 33339448-32697885(GRCh38)。②孕妇1携带的DMD基因部分重复，有数据库收录及相关文献报道其致病性；孕妇2携带的DMD基因部分重复，目前尚未见数据库收录，亦无对其致病性的文献报道。③对2个家系的分析结果发现，2例孕妇所在家系中，均有表型正常的成年男性携带相应DMD基因部分重复，故考虑这2种DMD基因部分重复致病的可能性小。

对于孕期携带者筛查中发现的临床意义不明(VUS)的DMD基因突变，分析孕妇家系成员相应DMD基因突变可为准确的遗传咨询提供依据，避免对其采取不必要的介入性产前诊断措施。

To explore the pathogenicity of partial duplication of dystrophin gene (called DMD gene) in pregnant women found by carrier screening.

From March to November 2022, two pregnant women (pregnant woman 1, 2) who carried partial duplication in the DMD gene found by carrier screening at Department of Prenatal Diagnosis, Nanjing Women and Children′s Healthcare Hospital were enrolled. Carriers were screened by capillary electrophoresis. Partial duplications in DMD gene were confirmed by multiplex ligation-dependent probe amplification (MLPA). The copy number variation (CNV) of DMD gene was detected by MLPA in 2 pregnant women′s family members, and a pedigree chart of the families carrying a partial duplication in DMD gene was drawn. Pathogenicity of gene mutation was classified according to Standards and Guidelines for the Interpretation of Sequence Variants set by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as ＂ACMG guidelines＂). The pathogenicity of the partial duplication in DMD gene was interpreted based on database records and their reported literature and clinical manifestations of males carrying the duplication. This study was reviewed and approved by the Ethics Committee of Nanjing Women and Children′s Healthcare Hospital [Approval No. (2020)KY-057)], and all participants signed written consent forms.

①Carrier screening identified that pregnant woman 1, 2 carried duplications of exon 1-6 and exon 1-9 in DMD gene, respectively, corresponding to ChrX: 33339448-32816399 (GRCh38) and ChrX: 33339448-32697885 (GRCh38). ② Duplication of exon 1-6 in DMD gene carried by pregnant woman 1 have been documented in databases and its pathogenicity was reported in related literature; however, duplication of exon 1-9 in DMD gene carried by pregnant woman 2 has not been recorded or reported. ③ Pedigree analysis showed that there were healthy males in two pregnant women′s family carrying the same duplications, suggesting those two duplications are likely to be non-pathogenic.

To provide accurate genetic counselling and avoid unnecessary invasive prenatal diagnosis measure, pedigree analysis of DMD gene duplications should be considered when carrier screening identified variants with variants of uncertain significance (VUS) in DMD gene.