Diagnosis of de novo fetal aceruloplasminemia via whole exome sequencing and fetal umbilical blood ceruloplasmin measurement

Summary Background Aceruloplasminemia is an autosomal recessive disorder, characterized by diabetes mellitus and progressive neurological symptoms, absent of phenotype before delivery. It is caused by mutations in CP , resulting in a deficiency in ceruloplasm. This study sought to diagnose sporadic fetal aceruloplasminemia via whole exome sequencing and plasma ceruloplasm measurement. Methods Amniotic fluid and cord blood samples were obtained from a 29-year-old woman. Trio-based whole exome sequencing was performed due to right aortic arch and left subclavian artery identified in fetal ultrasound scanning, on the maternal request. Plymerase chain reaction was performed on RNA, extracted from fetal cord blood and peripheral blood of the couple. Fetal cord blood ceruloplasmin, copper, iron and transferrin were determined by enzyme linked immunosorbent assay, nephelometric method and spectrometry, respectively. Ceruloplasmin was detected as control in twelve gestational age-matched normal fetal cord blood samples. Results No cardiac-related variants were identified, but two compound heterozygous CP variants (c.1306 C > T, p.(R436*) and c.3019-17T > G) were incidentally detected in the fetus. The c.1306 C > T p.(R436*) variant was a previously reported pathogenic variant that induced nonsense-mediated mRNA decay. The intronic variant (c.3019-17T > G), predicted by SpliceAI to disrupt splicing, was functionally confirmed to cause exon 18 skipping. Besides, ceruloplasmin concentrations in gestational week-matched healthy fetuses ranged from 2.75 to 56.18 mg/L (median: 14.93 mg/L, IQR: 9.96–21.43 mg/L), while it was undetectable (below the lower limit of detection) in the affected fetus. Copper and iron levels in affected fetus were within normal ranges, while transferrin levels were below the normal threshold. Conclusions Our findings expanded the spectrum of pathogenic variants in CP and provided new insights into the prenatal diagnosis of the aceruloplasminemia.