[Variant 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. Pathogenicity 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.