Genetic analysis of two fetuses with Mosaic variegated aneuploidy syndrome caused by compound heterozygous variants in BUB1B and its upstream regulatory elements and a literature Review.
10.3760/cma.j.cn511374-20240716-00393
- Author:
Jiangbo QU
1
,
2
;
Wenjuan ZHU
;
Ju WANG
;
Lu GAO
;
Dongyi YU
Author Information
1. Center for Medical Genetics and Prenatal Diagnosis of Shandong Maternal and Child Health Care Hospital (Key Laboratory of Birth Defect Prevention and Genetic Medicine of Shandong Provincial Health Commission, Key Laboratory of Maternal and Fetal Medicine of National Health Commission of China), Jinan, Shandong 250014, China. dongyi_yu@
2. com.
- Publication Type:English Abstract
- MeSH:
Humans;
Female;
Pregnancy;
Adult;
Mosaicism;
Protein Serine-Threonine Kinases/genetics*;
Chromosome Disorders/diagnosis*;
Pedigree;
Heterozygote;
Prenatal Diagnosis;
Aneuploidy;
Male;
Fetus;
Karyotyping
- From:
Chinese Journal of Medical Genetics
2025;42(4):446-453
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVE:To explore the genetic etiology of two fetuses with Mosaic variegated aneuploidy syndrome (MVA) in a pedigree.
METHODS:A 30-year-old pregnant woman, who presented at the Center for Medical Genetics and Prenatal Diagnosis of Shandong Maternal and Child Health Care Hospital on November 16, 2023, was enrolled. Clinical data of the pedigree were collected, and peripheral blood samples from the parents and amniotic fluid samples from the two fetuses were obtained for genomic DNA extraction. Whole exome sequencing (WES) was performed on both fetuses, followed by Sanger sequencing for familial validation and pathogenicity analysis of candidate variants. Chromosomal karyotyping of the parents was conducted to quantify the proportion of premature chromatid separation (PCS). This study was approved by the Medical Ethics Committee of Shandong Maternal and Child Health Care Hospital (Ethics No. 2024-034).
RESULTS:Both fetuses exhibited structural brain anomalies and developmental delays during the second trimester. Amniocyte karyotyping revealed low-level mosaic aneuploidy involving multiple chromosomes, while chromosomal microarray analysis (CMA) showed no abnormalities. Pregnancy termination was performed for fetus 1. WES identified compound heterozygous variants in BUB1B, i.e., c.2363_2364del (p.S788Cfs*29) and ss804270619: G>A, in both fetuses. Sanger sequencing confirmed paternal inheritance of c.2363_2364del and maternal inheritance of ss804270619:G>A. According to the American College of Medical Genetics and Genomics (ACMG) and Clinical Genome Resource (ClinGen) Standards and Guidelines for the Interpretation of Sequence Variants, the c.2363_2364del variant was classified as likely pathogenic (PVS1 + PM2_Supporting). Parental karyotyping demonstrated PCS traits, with a higher proportion of abnormal metaphases in the father.
CONCLUSION:The compound heterozygous variants c.2363_2364del (p.S788Cfs*29) and ss804270619: G>A in BUB1B may constitute the genetic etiology of the two MVA fetuses in this pedigree.
