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

Abstract Mosaic variegated aneuploidy (MVA) is a rare genetic disorder caused by mutations in BUB1B, CEP57, or TRIP13. We describe the prenatal diagnosis, molecular characterization, and clinical management of a long‐lived patient with BUB1B‐related MVA.


| INTRODUCTION
Mosaic variegated aneuploidy (MVA, OMIM 257300) is a congenital autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies, and monosomies, involving multiple chromosomes and tissues. 1 Mutations in BUB1B, CEP57, and TRIP13 genes, which are involved in mitotic spindle and microtubule stabilization, are responsible for the molecular pathogenesis of MVA. The clinical features of MVA syndrome include severe pre/postnatal growth retardation, microcephaly, central nervous system anomalies, intellectual disability, minor congenital malformation, and predisposition to malignancy. There is some genotype-phenotype correlation (Table 1). Intellectual disability, microcephaly, brain malformations, epilepsy, and cancer predisposition are more common in BUB1B subtype. Rhizomelic shortening of the upper limbs, skull anomalies with conserved head circumference, and absence of malignancy are more common in CEP57 subtype. In addition, TRIP13 subtype has growth retardation with microcephaly and developmental delay, but there is no other structural abnormality and dysmorphic facial feature as in BUB1B subtype.
Several cases of MVA were diagnosed in prenatal period, 2 followed by the termination of pregnancy. Here we reported a Chinese patient with the longest survival in literature, with cytogenetic and antenatal findings together with her longterm postnatal course and molecular finding.

| CASE REPORT
A 29-year-old multipara Chinese woman with two previous normal deliveries was referred for invasive prenatal diagnosis at 19 weeks of gestation in 1996. On antenatal screening, she was noted to have raised maternal serum alpha fetoprotein level of 3.08 MoM, abnormal fetal scan with early onset growth retardation, pericardial effusion and ascites, congenital heart disease, and duplication cyst of gut. Chromosome study of cultured amniotic fluid cells showed multiple cell line with a composite karyotype of 45~51,XX,+X [1],+2 [3],+3 [2],+5 [ Figure 1A). After counseling, the couple opted for keeping the fetus and the baby was delivered at 37 weeks with birthweight of 1.55 kg (<−3.6SD) and body length of 45 cm (<−3.2SD). Chromosome study of placental tissue showed a composite karyotype as 45~51,XX,− X [2],+1p [2],+1q [1] Based on the cytogenetic findings and clinical features, the clinical diagnosis of mosaic variegated aneuploidy syndrome was made. The proband was then regularly followed in pediatric and genetic department. At 8 months of age, she was diagnosed to have infantile neuroblastoma with surgical excision. She had failure to thrive and microcephaly all along. Developmental assessment at 2 years of age showed mild global developmental delay. She also had subtle facial dysmorphism (hypertelorism, high forehead, epicanthic fold, and midface hypoplasia) on physical examination ( Figure 1B). At 15 years old, she was diagnosed to have chronic glomerulosclerosis complicated with chronic renal failure that required renal transplant at 20 years old. At age 21, she developed pleural effusion, chylothorax, bilateral ovarian tumor (Meigs syndrome) with histological confirmation as Sertoli-Leydig cell tumor. Exome-sequencing analysis was performed on the DNA extracted from the peripheral blood of the patient. Compound heterozygous variants c.1402-5A>G and c.2386-11A>G in BUB1B gene were found ( Figure 2). Mother is a heterozygous c.2386-11A>G carrier while father is not available for testing.

| DISCUSSION
Premature chromatid separation (PCS) and asynchrony of mitotic stages is described to be the pathogenic mechanism for mosaic variegated aneuploidies (MVA). PCS/MVA manifests cytogenetically as a variety of mosaic aneuploidies, especially trisomies, double trisomies, and monosomies. The proportion of aneuploid cells varies but is usually >25% and is substantially greater than in normal individuals. Conventional cytogenetic analysis with at least two independent amniocyte cultures should always be performed to diagnose prenatal MVA. In our case, amniocyte, placenta, and cord blood lymphocytes culture demonstrated that the proportion of aneuploidy cells was more than 25%, which confirmed the prenatal diagnosis of MVA.
The phenotype is highly variable across individuals of MVA. Common abnormalities of MVA include intrauterine growth retardation, microcephaly, dysmorphic features, and mental retardation. There is also a high risk of early-onset childhood cancer like Wilms tumor, rhabdomyosarcoma, or leukemia. Facial dysmorphic features in MVA syndrome include micrognathia, frontal bossing, triangular face, epicanthic folds, hypertelorism, low-set ears, and broad nasal bridge. Cardiovascular, neurological, skeletal anomalies like rhizomelic shortening of the upper limbs, gastrointestinal, and dermatological anomalies, immunodeficiency, and endocrine problem like hypothyroidism have also been described. 3 Microcephaly was most commonly observed in MVA cases, described in general 90% patients. Prenatal ultrasound findings in association with MVA included intrauterine growth restriction, microcephaly, Dandy-Walker malformation, cerebral ventricular dilatation, fetal ascites, oligohydramnios, and increased nuchal translucency. According the literature on the prenatal cases of MVA, fetal growth restriction is the commonest feature. In this case, the main prenatal sonographic features include fetal growth restriction, microcephaly, pericardial effusion, ascites, and congenital heart disease. In the long-term follow-up of this patient, she manifested with failure to thrive, microcephaly, mild intellectual disability, and cancer predisposition. As the clinical phenotype is highly heterogeneous in MVA, especially in prenatal period, MVA syndrome is usually under-recognized and missed.
Genetic defect of chromosome segregation in cell mitosis might be associated with MVA, and mutations of BUB1B involved in the mitotic spindle checkpoint might underlie MVA. The compound heterozygous variants NM_001211.5(BUB1B):c.[1402-5A>G];[2387-11A>G] found in this patient are located at the RNA splicing acceptor site of exons 11 and 19 of BUB1B, and reported in the literature. 4,5 Reduced BUB1B expression on the spindle checkpoint is dose-dependent. An analogous mutation (in mice) to the human MVA BUB1B (encodes protein BUBR1) has a reduced lifespan and develop several age-related phenotypes at an accelerated rate. Sustained high expression of BUBR1 preserves genomic integrity and reduces tumorigenesis by correcting mitotic checkpoint impairment and microtubule-kinetochore attachment defects. 6 Clinical management of patients with MVA syndrome includes symptomatic support and tumor surveillance, particularly for BUB1B subtype. Early molecular diagnosis might enable risk stratification for tumor surveillance. Common tumors reported in BUB1B-associated MVA syndrome are Wilms tumor, rhabdomyosarcoma, leukemia and granulosa cell tumor of the ovary. In this case, patient suffered from infantile neuroblastoma and Sertoli-Leydig cell tumor. It is recommended that patients with MVA syndrome have regular abdominal ultrasound surveillance, to particularly look for Wilms tumor. However, as the incidence rate of other rare tumor in MVA is unknown, there is still no evidence to indicate that routine screening is beneficial. But high index of suspicion is necessary. In case there are any clinical symptoms of malignancy, further investigation should be carried out.
We have reported the longest Chinese survivor of BUB1Brelated MVA syndrome in the literature, its clinical course, and management.