UPD usually arises through initial meiotic segregation error.IsoUPD is caused by nondisjunction of sister chromatid in meiosis II,while hetUPD is caused by nondisjunction of homologous chromosomes in meiosis I.Trisomy rescue is one of the reasons for UPD and results from fertilization of a disomic spermatocyte and a normal oocyte in pat UPD.Subsequently, one of the supernumerary chromosomes is eliminated to restore the normal chromosomal number[3].The rescue events could occur after the division of the zygote and result in disomy/trisomy mosaicism.when a fetus has a normal karyotype and diagnosed with UPD, mosaicism usually may be found in multiple parts of the placenta biopsy.Trisomy mosaicism can lead to dysfunction of placental and bring about fetal growth restriction,heart malformation,skin edema,and so on[4, 5].So it is very important to keep an eye on the growth of the fetus and assess the maturity of the placenta when UPD is found.
IsoUPD inherited two identical copies of one homolog and harbors the risk of resulting in homozygosity for a chromosomal recessive disorders in the offspring of a heterozygous carrier. To date, there have been only 3 reported cases of recessive diseases resulting from pat UPD(3) with normal karyotype. One was a case of Pierson syndrome with distinct renal and ocular abnormalities caused by paternally-inherited homozygous mutation in the LAMB2 gene. The proband died from sepsis at 17 months[6]. Another was a 10-year-old girl with epilepsy, severe intellectual disability and progressive neurological decline caused by a homozygous pathogenic splice-site mutation in the GLB1 gene resulting mosaic pat UPD(3)[7]. In addition, microcytic anemia in a infant with sideroblastic anemia type 2 caused by rare nonsense homozygous variant of SLC25A38 gene resulting pat UPD(3)[8]. The three reported cases are definitely caused by single-gene disorders.Therefore, it is necessary to carry out further examination to exclude recessive gene pathogenic mutation when UPD is found in prenatal diagnosis.In our case,the fetus without abnormal ultrasound features at the whole gestation and the parents refused the further examination.So,we had to monitor and follow up the growth and development of the newborn.
As a rare abnormality,UPD leads to abnormal phenotype not only through homozygous recessive disorders,but also through gene imprinting.At present, identified chromosomes bearing imprinted genes include 6,7,11,14,15,and 20[9].However,only three imprinted genes predicted by bioinformatics on chromosome 3: two maternally expressed genes (ALDH1L and Z1C1) and one paternally expressed gene (HES1). No clear imprinted region and gene report were found.Currently,only one case of paternal UPD for entire chromosome 3 has been described with no apparent disease phenotype.The individual identified serendipitously in the study of a whole genome linkage scan and did not display any obvious adverse phenotypic disorders at age 42[10].Physical examination over the 1.5 years of our case has not shown any significant growth or developmental abnormalities, observations that suggest there is no important imprinted gene on paternal chromosome 3 that causes serious diseases. Nevertheless we will continue to follow this case to confirm this suggestion.
To sum up,the influence of UPD on a phenotype might be difficult to establish or predict in prenatal diagnosis, due to mosaicism for a trisomic cell line,to homozygosity for recessive pathogenic mutations,or to disorder of imprinted genes.The case we reported was the second case of complete paternal isoUPD(3) with no abnormality.Our study further evidenced that there were no important paternal imprinted genes causing rare genetic disorders on chromosome 3 and provides reference for the diagnosis and consultation of UPD(3) in prenatal diagnosis in the future.