[Clinical characteristics and genetic analysis of three fetuses with Baraitser-Winter cerebrofrontofacial syndrome and Dystonia-deafness syndrome type 1 due to variants of ACTB gene].

OBJECTIVE: To study the clinical and genetic characteristics of three fetuses with Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) and Dystonia-deafness syndrome type 1 (DDS1) due to variants of the β-actin (ACTB) gene.

METHODS: Two fetuses with BWCFF (fetuses 1 ~ 2) and one fetus with DDS1 (fetus 3) at the Affiliated Women and Children's Hospital of Ningbo University between July 2024 and September 2024 were enrolled as the study subjects. Amniotic fluid samples were collected from the fetuses, together with peripheral blood samples from the three couples. Chromosomal karyotyping and trio-whole-exome sequencing (trio-WES) were carried out. Candidate variants were verified by Sanger sequencing, and their pathogenicity was classified based on guidelines from the American College of Medical Genetics and Genomics (ACMG). Using "ACTB gene", "Baraitser-Winter brain frontal syndrome" and "dystonia-deafness syndrome" as the key words, relevant literature was retrieved from the PubMed Database, Wanfang Data Knowledge Service Platform, and the China National Knowledge Infrastruture (CNKI) database from their inception to 31 December 2024. A comprehensive analysis was conducted on the features of fetuses with BWCFF and DDS1 resulting from ACTB gene variants. This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: EC2024-184).

RESULTS: Fetal ultrasound revealed that fetus 1 had polycystic kidney and full-length ureteral dilation on the right side, fetus 2 had ventricular septal defect, and fetus 3 had pulmonary valve stenosis. Chromosomal karyotypes were normal in all cases. Trio-WES results revealed that the three fetuses had all harbored heterozygous missense variants of the ACTB gene, which were de novo in origin. Based on the guidelines from ACMG, the c.547C>T (p.Arg183Trp) carried by fetus 1 was classified as pathogenic (PM2_Supporting+PP2+PS3_Supporting+PS4_Moderate+PP4+PS2). The c.633C>G (p.Asp211Glu) variant carried by fetus 2 was classified as variant of uncertain clinical significance (PM2_Supporting+PS2_Supporting+PP3_Moderate+PP2), and so was the c.848T>C (p.Met283Thr) variant carried by fetus 3 (PM2_Supporting+PS2_Supporting+PP3_Moderate+PP2). By following the pre-set search strategy, 10 relevant articles reporting prenatal phenotypes of fetuses with ACTB variants were retrieved. Except the DDS1 fetus reported in the present study, all of remaining 15 fetuses (including two from this study) were diagnosed with BWCFF. Their common phenotypes included increased nuchal translucency/nuchal fold in 5 (33.3%), craniofacial anomalies (e.g., hypertelorism, microcephaly, cleft lip/palate) in 7 (46.7%), gastrointestinal anomalies in 6 (40.0%), urinary system abnormalites (e.g., hydronephrosis, renal cysts, pelviectasis) in 5 (33.3%), cardiovascular malformations (e.g., ventricular septal thickening, tricuspid regurgitation) in 6 (40.0), abnormal amniotic fluid volume in 4 (26.7%), and other abnormalities (e.g., hydrops fetalis, short femur, intrauterine growth restriction) in 3 (20%).

CONCLUSION: The ACTB gene variants c.547C>T, c.633C>G, and c.848T>C may be among the factors contributing to the ultrasound abnormalities observed in the fetuses. Among these, c.547C>T is a known pathogenic variant constituting to the genetic etiology of DDS1, whilst the c.633C>G and c.848T>C are both unreported previously. Trio-WES can enhance the prenatal diagnostic rates for DDS1 and BWCFF. Above finding has expanded the mutational spectrum of the ACTB gene and phenotypic spectrum of DDS1 and BWCFF.