Birth Defects: Moebius syndrome and related facial weakness disorders

描述（由申请人提供）：据估计，在美国大约每33个婴儿中就有1个有出生缺陷。其中，与面部无力和缺乏面部表情相关的出生缺陷综合征子集对社会交往和心理社会发展具有深远的影响。莫比乌斯综合征的定义是先天性和非进行性面部无力和有限的眼球外展，大多数病例被认为是由颅核/神经VI和VII功能障碍引起的。虽然罕见，但由于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、周围神经病变、肌肉张力低下、心脏缺陷、胸壁异常和肢体畸形，这种综合征会造成严重损害。表型谱和相关的遗传和环境因素的莫比乌斯综合征是知之甚少。本研究的目的是确定莫比乌斯综合征和相关疾病的致病基因突变，如莫比乌斯-波兰或-罗宾序列、遗传性先天性面部轻瘫（HCFP）和眼耳椎发育不良（Goldenhar综合征）。该提案建立在西奈山医学中心、波士顿儿童医院、NHGRI内部项目和莫比斯综合征基金会的研究人员之间正在进行的合作的基础上，但旨在通过与美国国立卫生研究院临床中心（CC）的研究人员合作，极大地扩展这项工作。我们的研究小组已经定义了一种新的常染色体显性综合征，包括莫比乌斯综合征、卡尔曼综合征、由TUBB3 E410K替代引起的周期性呕吐。我们还发现了一种新的常染色体隐性莫比斯综合征，由HOXB1 R207C替代引起双侧面瘫、听力损失和斜视。通过这些校外团队与校内研究人员的合作，对四个具有莫比乌斯样特征的家族进行了全外显子组测序（WES），数据分析正在进行中。这项新拨款申请的总体目标是每年对大约24个患有莫比斯综合征和其他未定义面部无力综合征的家族进行广泛的表型分析。将在中心进行的研究包括神经病学、精神病学、神经认知学、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;肌电图、神经传导和眨眼反射研究；眼动定量记录的视镜法；3D-CT颅面成像；脑、眼眶、内耳道、后窝MRI包括脑弥散张量成像；还有遗传咨询。与外部团队共同进行WES分析和变异确认。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）背后的分子途径产生重大影响。因此，这个项目将导致预防和治疗出生缺陷的策略。

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.