Prenatal diagnosis and long term follow up of a patient with mosaic variegated aneuploidy and its molecular analysis

Abstract

Objectives: Mosaic variegated aneuploidy (MVA) is a recessive condition characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple chromosomes and tissues. Mutations in BUB1B, CEP57 and TRIP13 genes are found in a subset of patients with MVA. The phenotype of MVA syndrome includes severe microcephaly and growth deficiency, central nervous system anomalies, mental retardation, mild physical anomalies, and predisposition to cancer. Several cases of MVA were diagnosed in prenatal period. We reported the cytogenetic and antenatal findings of a patient with MVA with long-term postnatal follow-up and molecular analysis result. Methods: A 29-year-old woman seen in 1996 at 19 weeks gestation because of raised maternal serum alpha-fetoprotein level was found to have fetal growth restriction with pericardial effusion. Amniocentesis was performed. Baby was born at 36 weeks with birth weight of 1.55 kg. Cord blood and placental tissue karyotype was repeated. She had infantile neuroblastoma, failure to thrive, microcephaly, short stature, mild mental insufficiency, renal failure, and was seen by clinical geneticist. At age 21, she developed pleural effusion, chylothorax, and bilateral ovarian tumour (Meigs syndrome), confirmed to be Sertoli-Leydig cell tumour. Targeted gene panel analysis on extended hereditary cancer syndrome was performed. Results: G-banded chromosome analysis on cultured amniocytes, placental tissue, and cord blood lymphocytes showed aneuploidies in multiple cell lines with composite karyotypes: 45~51,XX,+X[1],+2[3],+3[2],+5[6],-5[1],+6[4],-6[2],+7[6],+8[3],+10[3],+12[1],+14[1],+15[1],+16[1],+17[7],+18[1],+20[1],+21[2][cp150] in cultured amniocytes; 45~51,XX,-X[2],+1p[2],+1q[1],-1[2],+2[3],-2[3],+5[2],-5[3],+7[4],+8[9],+9[2],-10[2],+11[5],+12[4],+13[1],+14[1],-16[1],+17[3],+18[3],-18[1],+19[4],+20[5],+21[2],+fra[1][cp44] in cultured placental tissue, and 45~47,XX,-X[1],-13[1],+18[1],-21[1][cp8] in cord blood lymphocytes. Targeted gene panel analysis revealed biallelic pathogenic variants on BUB1B gene c.1402-5A>G and c.2386-11A>G. Conclusions: The case illustrated the clinical presentation of mosaic variegated aneuploidy syndrome from prenatal setting with intrauterine growth restriction, abnormal karyotypes on various tissues, to postnatal developmental problems including microcephaly, growth retardation and tumour formation. Pathogenic variants in BUB1B gene were detected.