Hildeberto Correia

Trisomy 15 mosaicism: Challenges in prenatal diagnosis

Keywords: trisomy 15 mosaicism; fetal mosaicism; chorionic villi; prenatal cytogenetics; SNP-array; uniparental disomy

Data supporting the co-expression of PDHA1 gene and of its paralogue PDHA2 in somatic cells of a family.

This article presents a dataset proving the simultaneous presence of a 5′UTR-truncated PDHA1 mRNA and a full-length PDHA2 mRNA in the somatic cells of a PDC-deficient female patient and all members of her immediate family (parents and brother). We have designed a large set of primer pairs in order to perform detailed RT-PCR assays allowing the clear identification of both PDHA1 and PDHA2 mRNA species in somatic cells. In addition, two different experimental approaches were used to elucidate the copy number of PDHA1 gene in the patient and her mother. The interpretation and discussion of these data, along with further extensive experiments concerning the origin of this altered gene expression and its potential therapeutic consequences, can be found in “Complex genetic findings in a female patient with pyruvate dehydrogenase complex deficiency: null mutations in the PDHX gene associated with unusual expression of the testis-specific PDHA2 gene in her somatic cells” (A. Pinheiro, M.J. Silva, C. Florindo, et al., 2016) [1].

Discordant Chromosome Placental Mosaicism in a Dichorionic Twin Pregnancy

Chorionic villus sampling (CVS) is now well established as aninvasive test for prenatal diagnosis of chromosome abnormalitiesand some authors argue that this first-trimester procedurehas several advantages over mid-trimester amniocentesis in twinpregnancies [Brambati et al., 2001]. Since twin gestations seem tohave a higher risk of chromosome aberrations when compared tosingleton pregnancies, some centers now offer the possibility offirst-trimester prenatal diagnosis using CVS, including molecularrapidaneuploidy(MRA)testingbyQF-PCRormultiplexligation-dependent probe amplification (MLPA). CVS may provide thepossibility of an earlier result which may be crucial for patientreassurance and pregnancy management but has the disadvantageoftheoccasionalpresenceofplacentalmosaicism,inaround1–2%of cases, that can result from analyzing a tissue chromosomallydifferent from that of the fetus [Ledbetter et al., 1992; Farraet al., 2000]. This mosaicism may affect only the placenta—confined placental mosaicism (CPM)—or extend to the fetus—true fetal mosaicism (TFM)—in the same or in a different degreefrom the one found in the placenta [Kalousek et al., 1989; Gratietal.,2006].CPMoccursasoneofthreeforms:(i)theabnormalcelllineisconfinedtocytotrophoblast(typeI);(ii)oritonlyaffectsthestromalvillouscore(mesenchyme;typeII);(iii)oritinvolvesboth(typeIII)[Gratietal.,2006].Non-mosaicismforeitherdiploidyoraneuploidyispossibleinthefetus.Thekaryotypeofthecelllineagesisusuallyobtainedbydirectpreparations/short-term(cytotropho-blast) or long-term (mesenchyme) CVS cultures. MRA testing ispossible and is thought to test a mixture of DNAs from both thevillouscytotrophoblastandmesenchymalcore[Mannetal.,2007].However, this may yield discrepant results from the full chromo-someanalysisdependingonthemethod,thelevelofmosaicismandthetypeoftissueusedforanalysis.Thedisomy–trisomymosaicismmay have a mitotic (CPM types I and II) or a meiotic origin(CPM type III). The latter is associated with an increased risk ofpregnancy complications and fetal uniparental disomy (UPD)[Grati et al., 2006]. The detection of mosaicism for the commonautosomal trisomies in prenatal samples is relatively rare but hasbeen reported previously, as well as false-positive findings oftrisomy 18 mosaicism in CVS analysis [Schuring-Blomet al., 2002]. On the other hand trisomy 2 is one of the mostfrequently involved trisomies in pseudomosaicism both in amni-otic fluid (AF) and CVS cultures [Benn and Hsu, 2004; Sifakisetal.,2010].ToourknowledgethisisthefirstreportofadiscrepantCPMinadichorionic(DC)twinpairthatinvolvesatrisomy18anda trisomy 2.The patient was a 31-year-old, primigravid woman with DCtwins,conceivedafteraninvitrofertilization(IVF)procedureduetosequelaefrompreviouspelvicinflammatorydisease.Ultrasoundexamination (USE) at 11 weeks showed an umbilical hernia/smallomphalocele in twin B and a smaller crown-rump length (CRL;39 mm vs. 48 mm in twin A, 20th and 50th centile, respectively).First trimester aneuploidy screening on the basis of maternal ageand fetal nuchal translucency yielded normal results for twin A(1/2,499) and not calculable for twin B because the CRL was<45 mm. Since an ultrasound abnormality and early growth