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A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report.
BMC Med Genet. 2020 09 17; 21(1):182.BM

Abstract

BACKGROUND

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene.

CASE PRESENTATION

Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon.

CONCLUSIONS

We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping.

Authors+Show Affiliations

Univ. Lille, CNRS, CHU Lille, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000, Lille, France.Stem Cell and Microenvironment Laboratory, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha, Qatar. Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), UMR_S 938, Centre de Recherche Saint-Antoine, Team Cancer Biology and Therapeutics, Institut Universitaire de Cancérologie, Sorbonne Université, F-75012, Paris, France. Nice Breast institute, 57 bld de la Californie, 06000, Nice, France.Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.INSERM IMRB U955-E10, UPEC - Université Paris Est, Faculté de Médicine, 94000, Créteil, France.Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.Univ. Lille, CNRS, CHU Lille, Institut Pasteur de Lille, UMR 8199 - EGID, F-59000, Lille, France. Department of Genomics of Common Disease, School of Public Health, Imperial College, South Kensington Campus, London, SW7 2AZ, UK.Epigenetics Cardiovascular Laboratory, Department of Genetic Medicine, Weill Cornell Medicine-Qatar, Doha, Qatar. Department of Human Genetics, Sidra Medical and Research Center, Doha, Qatar.Stem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.Gynécologie Obstétrique, HUPC, Hôpital Cochin, HUPC, Assistance Publique - Hôpitaux de Paris, Paris, France.Laboratoire d'ImmunoRhumatologie Moléculaire, plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), LabEx TRANSPLANTEX, Université de Strasbourg, 4 rue Kirschleger, 67085, Strasbourg, France.Stem cell and microenvironment laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. jat2021@qatar-med.cornell.edu. Department Genetic Medicine, Weill Cornell Medical College, New York, NY, USA. jat2021@qatar-med.cornell.edu.

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32943010

Citation

Jacob, Arthur, et al. "A De Novo Synonymous Variant in EFTUD2 Disrupts Normal Splicing and Causes Mandibulofacial Dysostosis With Microcephaly: Case Report." BMC Medical Genetics, vol. 21, no. 1, 2020, p. 182.
Jacob A, Pasquier J, Carapito R, et al. A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report. BMC Med Genet. 2020;21(1):182.
Jacob, A., Pasquier, J., Carapito, R., Auradé, F., Molitor, A., Froguel, P., Fakhro, K., Halabi, N., Viot, G., Bahram, S., & Rafii, A. (2020). A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report. BMC Medical Genetics, 21(1), 182. https://doi.org/10.1186/s12881-020-01121-y
Jacob A, et al. A De Novo Synonymous Variant in EFTUD2 Disrupts Normal Splicing and Causes Mandibulofacial Dysostosis With Microcephaly: Case Report. BMC Med Genet. 2020 09 17;21(1):182. PubMed PMID: 32943010.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A de novo synonymous variant in EFTUD2 disrupts normal splicing and causes mandibulofacial dysostosis with microcephaly: case report. AU - Jacob,Arthur, AU - Pasquier,Jennifer, AU - Carapito,Raphael, AU - Auradé,Frédéric, AU - Molitor,Anne, AU - Froguel,Philippe, AU - Fakhro,Khalid, AU - Halabi,Najeeb, AU - Viot,Géraldine, AU - Bahram,Seiamak, AU - Rafii,Arash, Y1 - 2020/09/17/ PY - 2019/11/12/received PY - 2020/09/03/accepted PY - 2020/9/18/entrez PY - 2020/9/19/pubmed PY - 2020/11/3/medline KW - Case report KW - EFTUD2 KW - Exonic splice enhancer variant KW - Mandibulofacial dysostosis with microcephaly KW - Synonymous splice variant KW - Whole-exome sequencing KW - de novo SP - 182 EP - 182 JF - BMC medical genetics JO - BMC Med Genet VL - 21 IS - 1 N2 - BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant genetic disease characterized by intellectual and growth retardations, as well as major microcephaly, induced by missense and splice site variants or microdeletions in the EFTUD2 gene. CASE PRESENTATION: Here, we investigate the case of a young girl with symptoms of MFDM and a normal karyotype. Whole-exome sequencing of the family was performed to identify genetic alterations responsible for this phenotype. We identified a de novo synonymous variant in the EFTUD2 gene. We demonstrated that this synonymous variant disrupts the donor splice-site in intron 9 resulting in the skipping of exon 9 and a frameshift that leads to a premature stop codon. CONCLUSIONS: We present the first case of MFDM caused by a synonymous variant disrupting the donor splice site, leading to exon skipping. SN - 1471-2350 UR - https://www.unboundmedicine.com/medline/citation/32943010/A_de_novo_synonymous_variant_in_EFTUD2_disrupts_normal_splicing_and_causes_mandibulofacial_dysostosis_with_microcephaly:_case_report_ DB - PRIME DP - Unbound Medicine ER -