[Genetic analysis for a pedigree with Structural heart defects and renal anomalies syndrome caused by variants of TMEM260 gene].

Objective: To explore the genetic characteristics of a fetus affected with Structural heart defects and renal anomalies syndrome (SHDRA).

Methods: A pedigree with SHDRA (fetus and the parents) who had visited the Affiliated Women and Children's Hospital of Ningbo University in April 2023 was selected as the study subject. Clinical data of the family were collected. A total of 10 mL of amniotic fluid cells from the fetus and 5 mL of peripheral blood samples from the parents were collected for genomic DNA extraction. Trio whole-exome sequencing (Trio-WES) was performed, and Sanger sequencing was used to validate candidate variants in the family. The identified variants were classified according to the Standards and Guidelines for the Interpretation of Sequence Variants established by the American College of Medical Genetics and Genomics (ACMG) (hereinafter referred to as the "ACMG Guidelines). Relevant research literature on SHDRA in domestic and international databases were searched for literature review. This study was approved by the Affiliated Women and Children's Hospital of Ningbo University (Ethics No. EC2023-094).

Results: In this family, prenatal ultrasound at 18 weeks of gestation revealed left renal multicystic dysplasia in the fetus. After birth, the infant exhibited an ostium secundum atrial septal defect, patent ductus arteriosus, and left renal multicystic dysplasia. Trio-WES revealed that the fetus had carried c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) compound heterozygous variants in the TMEM260 gene, which were respectively inherited from its father and mother. According to the ACMG guidelines, the c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants were classified as pathogenic (PM2_Supporting+PVS1+PP4) and likely pathogenic (PM2_Supporting+PM4+PM3+PP4), respectively. According to the literature search strategy set for this study, a total of 6 literature was retrieved, involving 25 SHDRA patients from 20 families. Together with the patients in this study, there were 14 TMEM260 gene variants, most of which were frameshift variants (7 types) and had located in exons 3, 11 and 13. The main clinical features of SHDRA were congenital heart malformation, renal abnormality and neurodevelopmental abnormality, and there was a lack of genotype-phenotype correlation.

Conclusion: The c.344dup (p.L116Afs*32) and c.90_104dup (p.Ala31_Ala35dup) variants of the TMEM260 gene probably underlay the SHDRA in this family. Above finding has provided a basis for clinical diagnosis and genetic counseling for the family.