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Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple:A case report

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World Journal of Clinical Cases 2021年第29期9卷 8797-8803页

作者： Adina Neumann Miguel angel Alcantara-Ortigoza ariadna gonzález-del angel Nestor Alejandro Zarate Díaz Javier Sam Santana Leonardo M Porchia Esther López-Bayghen Laboratorio de Investigación y Diagnóstico Molecular IngenesMexico City 05320Mexico Laboratorio de Biología Molecular Subdirección de Investigación MédicaInstituto Nacional de PediatríaMexico City 04530Mexico DNA-GEN S.C.Centro de Alta Especialidad en Genética Humana Mexico City 14070Mexico Investigación Clínica IngenesPuebla 72820Mexico Departamento de Toxicología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMexico City 07360Mexico

BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.

关键词： Propionic acidemia Autosomal recessive Propionyl-CoA carboxylase alpha subunit(PCCA)gene Preimplantation genetic testing Next-generation sequencing Embryo transfer

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Diagnosis of Laron syndrome using monoplex-polymerase chain reaction technology with a whole-genome amplification template: A case report

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World Journal of Clinical Cases 2019年第23期7卷 4029-4035页

作者： Adina Neumann Miguel angel Alcantara-Ortigoza ariadna gonzalez-del angel Felipe Camargo-Diaz Esther Lopez-Bayghen Laboratorio de Investigacion y Diagnostico Molecular Instituto de Infertilidad y Genetica Mexico SCINGENESMexico City 05320Mexico Instituto Nacional de Pediatria Torre de InvestigacionMexico City 04530Mexico Laboratorio de Biologia Molecular Departamento de Genetica HumanaInstituto Nacional de PediatriaMexico City 04530Mexico Departamento de Toxicologia Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional(CINVESTAV-IPN)Mexico City 07360Mexico

BACKGROUND Laron syndrome(LS)is an autosomal recessive hereditary condition affecting only 1/1000000 births.The cause is associated with mutations in the growth hormone(GH)receptor(GHR),leading to GH insensitivity.LS patients typically present with severe growth retardation,obesity,and abnormal sexual maturation.Currently,LS diagnosis is performed post-delivery.Therefore,we assessed the efficiency of Pre-implantation Genetic Testing(PGT)coupled with monoplex-polymerase chain reaction(PCR)technology for detecting this monogenic disease in embryos from a couple confirmed as LS heterozygous carriers CASE SUMMARY The couple LS-carriers were confirmed by the presence of a first child born with LS.The couple underwent a standard in vitro fertilization(IVF)protocol.DNA was collected from trophectoderm cells from day 5 embryos.Whole genome amplification(WGA)was performed using a Sureplex DNA Amplification System and analyzed by PCR,targeting the deletion of the exons 5 and 6 in the GHR gene as well as PGT by Next-generation Sequencing(Illumina).Eleven embryos were collected and analyzed.27.3%were the wild type for GHR,45.5%were heterozygotes,and 18.2%homozygous mutants.One embryo yielded no results.Three 2-embryos transfers were performed;2 normal homozygous and four heterozygous carriers were selected for transfer.The first two transfers were unsuccessful,whereas the final transfer with two heterozygous embryos resulted in clinical pregnancy.The genomic composition of the fetus was verified,applying the same techniques using amniocytes,extracted after 21 wk of the ongoing pregnancy.The fetus was confirmed as GHR deletion in exon 5-6,carrier.A non-affected baby was born.CONCLUSION Here,we present a case demonstrating that using WGA as a template in addition to PCR targeting specific gene regions,exons 5 and 6 on the GHR gene,could identify LS carrier embryos.This provides evidence that WGA and PCR serve as an excellent tool to detect this specific monogenic disease in IVF embryos,thus allowing selection of candidate embr

关键词： Growth hormone insensitivity Growth hormone receptor mutations Intragenic deletions Molecular diagnosis Embryo diagnosis Laron syndrome Case report

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