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Developmental defects
Original research
Preimplantation genetic testing for a chr14q32 microdeletion in a family with Kagami-Ogata syndrome and Temple syndrome
  1. Joan Sabria-Back1,
  2. Ana Monteagudo-Sánchez2,
  3. Marta Sánchez-Delgado2,
  4. Anne C Ferguson-Smith3,
  5. Olga Gómez1,
  6. Africa Pertierra Cartada1,
  7. Jair Tenorio4,5,6,
  8. Julián Nevado4,5,6,
  9. Pablo Lapunzina4,5,6,
  10. Arrate Pereda Aguirre7,
  11. Carles Giménez Sevilla8,
  12. Estefanía Toro Toro8,
  13. Guiomar Perez de Nanclares7,
  14. David Monk2,9
  1. 1 BCNatal, Barcelona Center for Maternal-Fetal and Neonatal Medicine, Hospital Sant Joan de Déu and Hospital Clinic, Barcelona, Spain
  2. 2 Cancer Epigenetics and Biology Program, Bellvitge Institute for Biomedical Research, Barcelona, Spain
  3. 3 Department of Genetics, University of Cambridge, Cambridge, Cambridgeshire, UK
  4. 4 INGEMM (Instituto de Genética Médica y Molecular), Hospital Universitario La Paz-IdiPaz, Hospital universitario la Paz, Madrid, Spain
  5. 5 CIBERER (Centro de Investigación Biomédica en Red de Enfermedades Raras), Madrid, Spain
  6. 6 ITHACA, European Reference Network on Rare Congenital Malformations and Rare Intellectual Disabilities, Madrid, Spain
  7. 7 Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Vitoria-Gasteiz, Spain
  8. 8 Reprogenetics, Barcelona, Spain
  9. 9 Biomedical Research Center, School of Biological Sciences, University of East Anglia, Norwich, UK
  1. Correspondence to Dr David Monk, University of East Anglia, Norwich NR4 7TJ, UK; d.monk{at}uea.ac.uk

Abstract

Introduction Kagami-Ogata syndrome (KOS14) and Temple syndrome (TS14) are two disorders associated with reciprocal alterations within the chr14q32 imprinted domain. Here, we present a work-up strategy for preimplantation genetic testing (PGT) to avoid the transmission of a causative micro-deletion.

Methods We analysed DNA from the KOS14 index case and parents using methylation-sensitive ligation-mediated probe amplification and methylation pyrosequencing. The extent of the deletion was mapped using SNP arrays. PGT was performed in trophectoderm samples in order to identify unaffected embryos. Samples were amplified using multiple displacement amplification, followed by genome-wide SNP genotyping to determine the at-risk haplotype and next-generation sequencing to determine aneuploidies.

Results A fully methylated pattern at the normally paternally methylated IG-DMR and MEG3 DMR in the KOS14 proband, accompanied by an unmethylated profile in the TS14 mother was consistent with maternal and paternal transmission of a deletion, respectively. Further analysis revealed a 108 kb deletion in both cases. The inheritance of the deletion on different parental alleles was consistent with the opposing phenotypes. In vitro fertilisation with intracytoplasmatic sperm injection and PGT were used to screen for deletion status and to transfer an unaffected embryo in this couple. A single euploid-unaffected embryo was identified resulting in a healthy baby born.

Discussion We identify a microdeletion responsible for multigeneration KOS14 and TS14 within a single family where carriers have a 50% risk of transmitting the deletion to their offspring. We show that PGT can successfully be offered to couples with IDs caused by genetic anomalies.

  • DNA methylation
  • epigenomics

Data availability statement

SNP array and NGS data are available on request.

https://doi.org/10.1136/jmedgenet-2020-107433

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    Data availability statement

    SNP array and NGS data are available on request.

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    Footnotes

    • Contributors OG, APC and JS-B were responsible for managing the clinical case and collecting samples. AM-S, MS-D, JT, JN, PL, APA and GPdeN performed the molecular characterisation of the family. CGS and ETT were responsible for the PGT-M. ACF-S supplied reagents for patient characterisation. DM performed molecular characterisation, coordinated the project and prepared the manuscript. All authors contributed to the final version of the manuscript.

    • Funding Work in the Monk laboratory was supported by Spanish Ministry of Economy and Competitiveness (MINECO; BFU2017-85571-R), co-funded with the European Union Regional Development Fund (FEDER). GPdeN and APA received funding from the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Economy and Competitiveness, co-financed by the European Regional Development Fund (PI16/00073) and a grant from the Department of Health of the Basque Government (GV2017/111040 to GPdN). PL and JT are recipients of the grant PI15/01481 of the ISCIII. AM-S was a recipient of an FPI PhD studentship from MINECO (BES-2015-072547).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

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