De novo c.2455C>T mutation of NPR2 gene in a fetus with shortened long bones and a ventricular septal defect conceived by a mother with a fragile site at 16q22.1 and a father with a rare heterochromatic variant of chromosome 4 from Vietnam

Abstract

Abstract Background A heterozygous natriuretic peptide receptor 2 (NPR2) gene c.2455C>T mutation was identified as a cause of familial idiopathic short stature (ISS). Only two cases with this mutation were reported previously, and the probands with ISS had no organ system defects. Methods Next‐generation sequencing (NGS) was performed on an amniotic fluid DNA sample of a fetus with shortened long bones and a small ventricular septal defect detected by an obstetric ultrasound examination. The pathogenic variant of the fetus was confirmed by Sanger sequencing. Sanger sequencing, G‐banded, and C‐banded karyotyping of the fetus's parents were subsequently performed. Results A de novo NPR2 gene c.2455C>T, p.(Arg819Cys) mutation was identified in the fetus. No microdeletion or microduplication was identified in the fetus by copy number variation sequencing with a maximum resolution of 400 kb. The two previous miscarriages experienced by the fetus's parents were interpreted as a result of chromosomal aberrations, including a maternal fragile site at 16q22.1 and a rare paternal variant involving in a large G‐band‐positive and C‐band‐positive block of paracentric heterochromatin of chromosome 4p. Conclusion This report provides clinical signs of a de novo heterozygous NPR2 gene c.2455C>T mutation in the fetus and shows paternal chromosomal aberrations causing repeated pregnancy loss.

Keywords

• fragile site at 16q22.1
• NPR2 gene c.2455C>T
• repeated pregnancy loss
• shortened long bones
• variant of paracentric heterochromatin of chromosome 4p