目的 探究2个脊髓性肌萎缩伴呼吸窘迫1型(SMARD1)家系的遗传学病因，并预防出生缺陷。 方法 选取2021年8月至11月于南京大学医学院附属鼓楼医院妇产医学中心就诊的2个无亲缘关系的家系为研究对象。运用多重连接依赖探针扩增技术(MLPA)检测先证者及其家系成员SMN1基因第7外显子的拷贝数，通过全外显子组测序(WES)对先证者进行基因检测，并对家系成员行Sanger测序验证分析，对变异位点进行生物信息学分析。依据上述检测与分析结果，对家系中再次妊娠的胎儿行介入性产前诊断。 结果 基因检测发现2例先证者均携带IGHMBP2基因复合杂合变异，分别遗传自父母。其中变异c.1144C>T、c.866delG和c.1666C>G既往未见报道，根据美国医学遗传学与基因组学学会变异相关指南分别评为致病性变异(PVS1＋PM2_Supporting＋PP3＋PP4)、可能致病性变异(PM1＋PM2_Supporting＋PM4＋PP3＋PP4)和可能致病性变异(PM1＋PM2_Supporting＋PP2＋PP3＋PP4)。通过胚胎植入前单基因遗传学检测(PGT-M)和介入性产前诊断成功阻断了变异在家系中的传递，有效预防了出生缺陷的发生。 结论 该2例考虑是由IGHMBP2基因复合杂合变异导致的SMARD1，为SMARD1的鉴别诊断和家系遗传咨询提供重要依据。 Objective To explore the genetic etiology of two children with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), and prevent the recurrence of birth defects. Methods Two unrelated families who had visited the Obstetrics and Gynecology Medical Center of Drum Tower Hospital from August to November 2021 were selected as the study subjects. Copy number of SMN1 gene exon 7 for the probands and their parents was detected by multiple ligation-dependent probe amplification (MLPA). and whole exome sequencing (WES) was carried out to screen the variants in the probands. Sanger sequencing was used to validate the variants within the families. Pathogenecity of the variants were predicted by bioinformatic analysis. Based on the results, prenatal diagnosis was performed for the fetuses. Results Both probands were found to harbor compound heterozygous variants of the IGHMBP2 gene, which were inherited from their parents. Among these, c. 1144C>T, c. 866delG and c. 1666C>G were previously unreported and respectively classified as pathogenic variant (PVS1+ PM2_Supporting+ PP3+ PP4), likely pathogenic variant (PM1+ PM2_Supporting+ PM4+ PP3+ PP4) and likely pathogenic variant (PM1+ PM2_Supporting+ PP2+ PP3+ PP4) based on the ACMG guidelines. Through preimplantation genetic testing for monogenic (PGT-M) and interventional prenatal diagnosis, transmission of the variants within the families was successfully blocked. Conclusion The SMARD1 in both children may be attributed to the compound heterozygous variants of the IGHMBP2 gene, which has facilitated the genetic diagnosis and counselling, and provided reference for delineating the molecular pathogenesis of this disease.
Variants analysis and prenatal diagnosis for two Chinese pedigrees affected with Spinal muscular atrophy with respiratory distress type 1
Objective To explore the genetic etiology of two children with Spinal muscular atrophy with respiratory distress type 1 (SMARD1), and prevent the recurrence of birth defects. Methods Two unrelated families who had visited the Obstetrics and Gynecology Medical Center of Drum Tower Hospital from August to November 2021 were selected as the study subjects. Copy number of SMN1 gene exon 7 for the probands and their parents was detected by multiple ligation-dependent probe amplification (MLPA). and whole exome sequencing (WES) was carried out to screen the variants in the probands. Sanger sequencing was used to validate the variants within the families. Pathogenecity of the variants were predicted by bioinformatic analysis. Based on the results, prenatal diagnosis was performed for the fetuses. Results Both probands were found to harbor compound heterozygous variants of the IGHMBP2 gene, which were inherited from their parents. Among these, c. 1144C>T, c. 866delG and c. 1666C>G were previously unreported and respectively classified as pathogenic variant (PVS1+ PM2_Supporting+ PP3+ PP4), likely pathogenic variant (PM1+ PM2_Supporting+ PM4+ PP3+ PP4) and likely pathogenic variant (PM1+ PM2_Supporting+ PP2+ PP3+ PP4) based on the ACMG guidelines. Through preimplantation genetic testing for monogenic (PGT-M) and interventional prenatal diagnosis, transmission of the variants within the families was successfully blocked. Conclusion The SMARD1 in both children may be attributed to the compound heterozygous variants of the IGHMBP2 gene, which has facilitated the genetic diagnosis and counselling, and provided reference for delineating the molecular pathogenesis of this disease.
Spinal muscular atrophy with respiratory distress type 1IGHMBP2 genePrenatal diagnosis
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