Abstract:

Objective: A fetus was suggested the developmental abnormity of skeletal system and suspected growth restriction by prenatal B-ultrasound. To clarify the cause of the disease, genetic detection and bioinformatics analysis were conducted. Methods: gDNAs were extracted from the amniotic fluid of proband and the peripheral blood of his parents, respectively. Whole exome sequencing (WES) and copy number variation sequencing (CNV-seq) technique of trio via high-throughput sequencing platforms, and Sanger sequencing were used to verify the likely pathogenic variant. Results: A denovo mutation of c.223C>T(p.R75W) in the fetal high mobility group protein AT-Hook-2(HMGA2) gene was found. It is a missense mutation, resulting in the change of amino acid to p.R75W (p.Arg75Trp). According to American College of Medical Genetics and Genomics (ACMG), the variant was assessed to be a likely pathogenic variant: PS2+PM2_Supporting+PP3+PS4_Supporting. Based on the clinical phenotype, the fetus was diagnosed with an autosomal dominant Silver-Russell syndrome 5 (SRS5). Sanger sequencing confirmed the authenticity of the mutation. Conclusions: The c.223C>T(p.R75W) of HMGA2 gene may be the genetic cause of the heterozygous pathogenic variation, which expands the variant profile of this gene and provides a theoretical basis for prenatal genetic counseling and subsequent interventions in the fetus.

Key words: Silver-Russell syndrome, High mobility group proteins, Whole exome sequencing, DNA copy number variations, Fetal growth retardation