Birth Defects: Moebius syndrome and related facial weakness disorders

描述(由申请人提供)：据估计，在美国，每33个婴儿中就有一个出生时有缺陷。其中，与面部虚弱和缺乏面部表情相关的出生缺陷综合征的子集可能会对社会互动和心理社会发展产生深远的影响。Moebius综合征的定义是先天性和非进行性面部无力和有限的眼睛外展，大多数病例被认为是由颅核/神经VI和VII的功能障碍引起的。虽然罕见，但这种综合征会因面部无力和相关的智力障碍、自闭症、听力损失、吞咽和呼吸困难、周围神经病、肌肉张力减退、心脏缺陷、胸壁异常和肢体畸形而导致显著的损害。Moebius综合征的表型谱以及相关的遗传和环境因素知之甚少。这项研究的目的是确定Moebius综合征和相关疾病的致病基因突变，如Moebius-波兰或-Robin序列、遗传性先天性面瘫(HCFP)和眼耳脊椎发育不良(Goldenhar综合征)。这项建议建立在西奈山医学中心、波士顿儿童医院、NHGRI内科项目和莫比乌斯综合征基金会的研究人员之间持续合作的基础上，但旨在通过与NIH临床中心(CC)的研究人员合作来极大地扩展这一工作。我们的研究小组已经定义了一种新的常染色体显性遗传综合征，即Moebius综合征、Kallmann综合征、由TUBB3 E410K替换引起的周期性呕吐。我们还发现了一种新的常染色体隐性遗传Moebius相关综合征，由HOXB1 R207C替换导致双侧面瘫、听力损失和斜视。通过这些校外团队与内部研究人员的合作，已经对四个具有Moebius样特征的家庭进行了完整的外显子组测序，数据分析正在进行中。这项新赠款申请的总体目标将是每年对大约24个患有Moebius和其他面部无力的不明综合征的家庭进行广泛的表型分析。将在CC进行的研究包括神经学、精神病学、神经认知、康复医学(肌肉力量、言语/语言病理学)、眼科、听力学和遗传学评估；自闭症筛查；肌电、神经传导和瞬目反射研究；定量眼球运动记录的视频检查；3D-CT颅面成像；大脑、眼眶、内耳道、后颅窝的MRI，包括脑部扩散张量成像；以及遗传咨询。将与校外团队一起进行WES分析和变体确认。对这些出生缺陷的表型和基因型谱的更全面的定义将对我们理解畸形、脑神经发育和更常见的儿童疾病(如自闭症)的分子途径产生重大影响。因此，该项目将导致制定预防和治疗出生缺陷的战略。

DESCRIPTION (provided by applicant): It is estimated that about 1 in every 33 infants in the United States is born with a birth defect. Among these, the subset of birth defect syndromes associated with facial weakness and lack of facial expression can have profound implications for social interactions and psychosocial development. Moebius syndrome is defined by congenital and non-progressive facial weakness and limited eye abduction, and most cases are believed to result from dysfunction of cranial nuclei/nerves VI and VII. Although rare, this syndrome causes significant impairment because of facial weakness and associated intellectual disabilities, autism, hearing loss, difficulty swallowing and breathing, peripheral neuropathy, muscle hypotonia, heart defects, chest wall abnormalities, and limb malformations. The phenotypic spectrum and the associated genetic and environmental factors underlying Moebius syndrome are poorly understood. The goal of this research is to identify causative gene mutations for Moebius syndrome and related conditions, such as Moebius-Poland or -Robin sequence, hereditary congenital facial paresis (HCFP), and oculoauriculovertebral dysplasia (Goldenhar syndrome). This proposal builds on an ongoing collaboration among researchers at Mount Sinai Medical Center, Boston Children's Hospital, NHGRI intramural program, and the Moebius Syndrome Foundation, but aims to greatly extend that work by collaboration with investigators in the NIH Clinical Center (CC). Our groups have already defined a new autosomal dominant syndrome with Moebius syndrome, Kallmann syndrome, cyclic vomiting resulting from a TUBB3 E410K substitution. We have also identified a new autosomal recessive Moebius- related syndrome with bilateral facial palsy, hearing loss, and strabismus resulting from a HOXB1 R207C substitution. Through collaborative efforts of these extramural teams with intramural investigators, whole exome sequencing (WES) has been conducted for four families with Moebius-like features, and data analyses are ongoing. The overall goal of this new grant application will be to conduct extensive phenotype analysis on approximately 24 families per year with Moebius and other undefined syndromes with facial weakness. Studies to be conducted at the CC include neurology, psychiatry, neurocognitive, rehabilitation medicine (muscle strength, speech/language pathology), ophthalmology, audiology, and genetics evaluations; autism screening; electromyography, nerve conduction, and blink reflex studies; videoscopy of quantitative eye movement recordings; 3D-CT craniofacial imaging; MRI of the brain, orbit, internal auditory canals, posterior fossa including brain diffusion tensor imaging fo tractography; and genetic counseling. Jointly with the extramural teams, WES analysis and variant confirmation will be performed. A more comprehensive definition of the phenotypic and genotypic spectrum of these birth defects will have a significant impact on our understanding of the molecular pathways underlying dysmorphologies, cranial nerve development, and more common childhood disorders such as autism. Thus, this project will lead to strategies for prevention and treatment of birth defects.