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).
CONCLUSIONS: 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.
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).
CONCLUSIONS: 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.
摘要：
背景：下颌面骨发育不全伴小头畸形（MFDM）是一种罕见的多发性畸形综合征，其特征是由（延伸因子TuGTP结合域-含2）EFTUD2的单倍功能不全引起的颌骨和下颌骨发育不全以及先天性或出生后的小头畸形。
方法：我们报告了一个16个月大男孩的MFDM症状，包括颌骨和下颌骨发育不全，小头畸形,小颌畸形,中线腭裂，microtia,耳道闭锁,严重的感觉神经性听力损失,和发育迟缓。对患者家族进行全外显子组测序（WES）分析，以确定导致该表型的遗传病因。
结果：我们鉴定了一种新的从头错义突变（c.671G>T，p.Gly224Val)在EFTUD2中。根据美国医学遗传学和基因组学学院(ACMG)2015年指南，c.671G>T突变被分类为可能致病(PS2,PM1,PM2和PP3).根据我们的发现,对先证者父母的第二个婴儿进行产前诊断以排除突变,并在随访14个月后证实该婴儿不具有MFDM表型.此外，斑马鱼模型证实EFTUD2c.671G>T突变导致EFTUD2基因功能丧失，EFTUD2c.671G>T突变的致病性被归类为致病性(PS2、PS3、PM1和PM2)。
结论：我们的结果表明，WES是鉴定潜在致病性突变的有用工具，特别是在罕见疾病中，有利于遗传咨询和后续产前诊断。此外，功能测定的重要性不可低估，这可以进一步证实遗传变异的致病性。
方法：我们报告了一个16个月大男孩的MFDM症状，包括颌骨和下颌骨发育不全，小头畸形,小颌畸形,中线腭裂，microtia,耳道闭锁,严重的感觉神经性听力损失,和发育迟缓。对患者家族进行全外显子组测序（WES）分析，以确定导致该表型的遗传病因。
结果：我们鉴定了一种新的从头错义突变（c.671G>T，p.Gly224Val)在EFTUD2中。根据美国医学遗传学和基因组学学院(ACMG)2015年指南，c.671G>T突变被分类为可能致病(PS2,PM1,PM2和PP3).根据我们的发现,对先证者父母的第二个婴儿进行产前诊断以排除突变,并在随访14个月后证实该婴儿不具有MFDM表型.此外，斑马鱼模型证实EFTUD2c.671G>T突变导致EFTUD2基因功能丧失，EFTUD2c.671G>T突变的致病性被归类为致病性(PS2、PS3、PM1和PM2)。
结论：我们的结果表明，WES是鉴定潜在致病性突变的有用工具，特别是在罕见疾病中，有利于遗传咨询和后续产前诊断。此外，功能测定的重要性不可低估，这可以进一步证实遗传变异的致病性。
