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A novel de novo missense mutation in EFTUD2 identified by whole-exome sequencing in mandibulofacial dysostosis with microcephaly.
J Clin Lab Anal. 2022 May; 36(5):e24440.JC

Abstract

BACKGROUND

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare multiple malformation syndrome characterized by malar and mandibular hypoplasia and congenital- or postnatal-onset microcephaly induced by haploinsufficiency of (elongation factor Tu GTP-binding domain-containing 2) EFTUD2.

METHODS

We report the case of a 16-month-old boy with MFDM symptoms, including malar and mandibular hypoplasia, microcephaly, micrognathia, midline cleft palate, microtia, auditory canal atresia, severe sensorineural hearing loss, and developmental delay. Whole-exome sequencing (WES) analysis of the patient's family was performed to identify the genetic etiology responsible for this phenotype.

RESULTS

We identified a novel de novo missense mutation (c.671G>T, p.Gly224Val) in the EFTUD2. According to the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines, the c.671G>T mutation was classified as likely pathogenic (PS2, PM1, PM2, and PP3). Based on our findings, prenatal diagnosis was performed on the second baby of the proband's parents to exclude the mutation and it was confirmed that the baby did not have the MFDM phenotype after 14 months of follow-up. Furthermore, the zebrafish model confirmed that the EFTUD2 c.671G>T mutation caused a loss of gene function in EFTUD2, and the pathogenicity of the EFTUD2 c.671G>T mutation was classified as pathogenic (PS2, PS3, PM1, and PM2).

CONCLUSION

Our results indicate that WES is a useful tool for identifying potentially pathogenic mutations, particularly in rare disorders, and is advantageous for genetic counseling and subsequent prenatal diagnosis. Moreover, the importance of functional assays cannot be underestimated, which could further confirm the pathogenicity of the genetic variants.

Authors+Show Affiliations

Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China. SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China. SCU-CUHK Joint Laboratory for Reproductive Medicine, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China.Department of Medical Genetics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China. Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.

Pub Type(s)

Case Reports

Language

eng

PubMed ID

35435265

Citation

Yang, Mei, et al. "A Novel De Novo Missense Mutation in EFTUD2 Identified By Whole-exome Sequencing in Mandibulofacial Dysostosis With Microcephaly." Journal of Clinical Laboratory Analysis, vol. 36, no. 5, 2022, pp. e24440.
Yang M, Liu Y, Lin Z, et al. A novel de novo missense mutation in EFTUD2 identified by whole-exome sequencing in mandibulofacial dysostosis with microcephaly. J Clin Lab Anal. 2022;36(5):e24440.
Yang, M., Liu, Y., Lin, Z., Sun, H., & Hu, T. (2022). A novel de novo missense mutation in EFTUD2 identified by whole-exome sequencing in mandibulofacial dysostosis with microcephaly. Journal of Clinical Laboratory Analysis, 36(5), e24440. https://doi.org/10.1002/jcla.24440
Yang M, et al. A Novel De Novo Missense Mutation in EFTUD2 Identified By Whole-exome Sequencing in Mandibulofacial Dysostosis With Microcephaly. J Clin Lab Anal. 2022;36(5):e24440. PubMed PMID: 35435265.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel de novo missense mutation in EFTUD2 identified by whole-exome sequencing in mandibulofacial dysostosis with microcephaly. AU - Yang,Mei, AU - Liu,Yanyan, AU - Lin,Ziyuan, AU - Sun,Huaqin, AU - Hu,Ting, Y1 - 2022/04/18/ PY - 2022/03/10/revised PY - 2021/12/20/received PY - 2022/04/05/accepted PY - 2022/4/19/pubmed PY - 2022/5/18/medline PY - 2022/4/18/entrez KW - EFTUD2 KW - mandibulofacial dysostosis with microcephaly KW - missense mutation KW - prenatal diagnosis KW - whole-exome sequencing SP - e24440 EP - e24440 JF - Journal of clinical laboratory analysis JO - J Clin Lab Anal VL - 36 IS - 5 N2 - BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is a rare multiple malformation syndrome characterized by malar and mandibular hypoplasia and congenital- or postnatal-onset microcephaly induced by haploinsufficiency of (elongation factor Tu GTP-binding domain-containing 2) EFTUD2. METHODS: We report the case of a 16-month-old boy with MFDM symptoms, including malar and mandibular hypoplasia, microcephaly, micrognathia, midline cleft palate, microtia, auditory canal atresia, severe sensorineural hearing loss, and developmental delay. Whole-exome sequencing (WES) analysis of the patient's family was performed to identify the genetic etiology responsible for this phenotype. RESULTS: We identified a novel de novo missense mutation (c.671G>T, p.Gly224Val) in the EFTUD2. According to the American College of Medical Genetics and Genomics (ACMG) 2015 guidelines, the c.671G>T mutation was classified as likely pathogenic (PS2, PM1, PM2, and PP3). Based on our findings, prenatal diagnosis was performed on the second baby of the proband's parents to exclude the mutation and it was confirmed that the baby did not have the MFDM phenotype after 14 months of follow-up. Furthermore, the zebrafish model confirmed that the EFTUD2 c.671G>T mutation caused a loss of gene function in EFTUD2, and the pathogenicity of the EFTUD2 c.671G>T mutation was classified as pathogenic (PS2, PS3, PM1, and PM2). CONCLUSION: Our results indicate that WES is a useful tool for identifying potentially pathogenic mutations, particularly in rare disorders, and is advantageous for genetic counseling and subsequent prenatal diagnosis. Moreover, the importance of functional assays cannot be underestimated, which could further confirm the pathogenicity of the genetic variants. SN - 1098-2825 UR - https://www.unboundmedicine.com/medline/citation/35435265/A_novel_de_novo_missense_mutation_in_EFTUD2_identified_by_whole_exome_sequencing_in_mandibulofacial_dysostosis_with_microcephaly_ DB - PRIME DP - Unbound Medicine ER -