Mandibulofacial dysostosis with microcephaly (MFDM) is a rare genetic disorder inherited in an autosomal dominant pattern. Major characteristics include developmental delay, craniofacial malformations such as malar and mandibular hypoplasia, and ear anomalies. Here, we report a 4.5-yr-old female patient with symptoms fitting MFDM. Using whole-genome sequencing, we identified a de novo start-codon loss (c.3G > T) in the EFTUD2 We examined EFTUD2 expression in the patient by RNA sequencing and observed a notable functional consequence of the variant on gene expression in the patient. We identified a novel variant for the development of MFDM in humans. To the best of our knowledge, this is the first report of a start-codon loss in EFTUD2 associated with MFDM.

Objective:To explore the clinical diagnosis, otological treatment and molecular etiology in a rare syndromic hearing loss case characterized by mandibulofacial dysostosis with microcephaly（MFDM）. Methods: The proband underwent detailed history collection, systematic physical examination and phenotypic analysis, as well as audiological examination, chest X-ray, temporal bone CT and brain MRI and other imaging examinations. The blood DNA of the proband and his parents was extracted and tested by the whole exom sequencing. The EFTUD2-related-MFDM literatures published by the end of 2020 were searched and sifted in PubMed and CNKI databases,the clinical characteristics of MFDM were summarized. Results:In this study, the patient presented with hypoplasia of auricle, micrognathia, microcephaly, developmental retardation, severe sensorineural hearing loss in both ears, and developmental malformation of middle and inner ear. Genetic analysis revealed a de novo deletion c.623_624delAT in EFTUD2 gene. According to the clinical features and genetic test results, the patient was diagnosed as MFDM. In order to solve the problem of hearing loss, the patient was further performed bilateral cochlear implantation, and part of the electrodes responded well during and after operation. Conclusion:This is the first domestic reported case of MFDM caused by EFTUD2 gene mutation. The key problem of cochlear implantation for this kind of patient is to avoid damaging the malformed facial nerve during the operation.The effect of speech rehabilitation after cochlear implant operation is related to many factors such as intelligence development of the patients.
目的：分析探讨罕见的下颌骨颜面发育不全伴小头畸形（MFDM）的临床诊断、耳科学治疗以及分子病因学特征。 方法：对先证者进行详细的病史采集，系统查体及表型特征分析，以及听力学检查，胸部X线、颞骨CT和颅脑MRI等影像学检查。同时提取先证者及其父母血液DNA进行全外显子组测序，并检索PubMed、中国知网数据库，对截止2020年底前报道的由EFTUD2基因突变导致的MFDM临床特征进行筛选、归纳和总结。 结果：患儿表现为耳廓发育不良、小下颌、小头畸形，同时合并发育迟缓、双耳极重度感音神经性聋，中耳及内耳发育畸形，基因学检测发现EFTUD2基因的新生缺失变异c.623_624delAT。根据临床特征及基因学检测结果诊断为MFDM。行双侧人工耳蜗植入手术，术中及开机后部分电极反应良好。 结论：这是国内首次报道的EFTUD2基因突变导致的MFDM，对该患儿进行人工耳蜗植入术的关键在于术中避免损伤畸形的面神经，术后言语康复效果与患儿智力发育等多因素相关。.

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

Mandibulofacial dysostosis with microcephaly (MFDM) is a rare autosomal dominant condition that was first described in 2006. The causative gene, EFTUD2, identified in 2012. We report on a family that initially presented to a pediatric genetics clinic in the 1980s for evaluation of multiple congenital anomalies. Re-evaluation of one member thirty years later resulted in a phenotypic and molecularly confirmed diagnosis of MFDM. This family\'s clinical histories and the novel EFTUD2 variant identified, c.1297_1298delAT (p.Met433Valfs*17), add to the literature about MFDM. This case presented several genetic counseling challenges and highlights that \"the patient\" can be multiple family members. We discuss testing considerations for an unknown disorder complicated by the time constraint of the patient\'s daughter\'s pregnancy and how the diagnosis changed previously provided recurrence risks. Of note, 1) the 1980s clinic visit letters provided critical information about affected family members and 2) the patient\'s husband\'s internet search of his wife\'s clinical features also yielded the MFDM diagnosis, illustrating the power of the internet in the hands of patients. Ultimately, this case emphasizes the importance of re-evaluation given advances in genetics and the value of a genetic diagnosis for both patient care and risk determination for family members.

We report a case of mandibulofacial dysostosis with microcephaly presenting with seizures. The proband, a 6-year-old Korean boy, had microcephaly, malar and mandibular hypoplasia, and deafness. He showed developmental delay and had suffered recurrent seizures beginning at 21months of age. Electroencephalography revealed occasional spike discharges from the right frontal area. Head magnetic resonance imaging revealed dilatation of the lateral ventricles and a small frontal lobe volume. Whole exome sequencing revealed a de novo frame shift mutation, c.2698_2701 del, of EFTUD2. The epileptic focus was consistent with the reduced frontal lobe volume on head magnetic resonance imaging. Seizures are thus a main feature of mandibulofacial dysostosis with microcephaly, which results from an embryonic development defect due to the EFTUD2 mutation.

In this work, we address the question of whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologous G domains of different stability: the mesophilic G domain of the elongation factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-1α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time scale, we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favorable for both systems, with the hyperthermophilic protein offering a slightly more favorable environment to host water molecules. We estimate that, under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that, at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that under extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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