Genetic Etiologies of Horizontal Strabismus

描述（由申请人提供）：先天性斜视是与双眼视觉丧失相关的眼睛的病理性错位。它影响了全球4%的人口和美国600万至1200万人，并且可以降低单眼或双眼的视力，损害深度感知，扰乱人际交往和自尊。先天性斜视可分为斜视型和非斜视型。不稳定型占病例的2%，并且受影响的个体具有有限的眼球运动，使得角度随注视方向而变化。先天性共同性斜视（CCS）占病例的98%，受影响的个体具有完整的眼球运动，随着注视方向的变化，未对准的角度保持恒定。它包括内斜视、外斜视和单视综合征。对罕见形式的非共同性斜视的遗传和神经发育研究表明，它可能是由对眼颅运动神经元发育以及对发育中的轴突的适当生长和引导至关重要的基因突变引起的。相比之下，尽管其发病率高，发病率高，社会损失的生产力成本高，CCS的潜在遗传因素仍然是一个谜。人群、家族和双胞胎研究都支持CCS的强遗传贡献，先证者一级亲属的相对风险估计在3到5之间。CCS是非常适合以家庭为基础的分析，因为它的发病年龄早，家庭复发率高，家庭成员的招募容易。因此，目前的提案旨在利用现有的基础设施和多学科团队：（1）扩大CCS的临床和遗传研究的确定和表型分析;（2）获取和管理CCS的全基因组基因型数据;（3）通过全基因组纯合性作图和连锁分析鉴定CCS的罕见遗传变异;（4）通过全基因组关联研究（genome-wide association study，GWAS）确定与内斜视相关的常见变异。更好地了解CCS的遗传病因应该提供深入了解其神经发育基础，并可能对人口的健康和福祉产生深远的积极影响。识别高危患者或家庭将提高筛查计划的效率，从而能够更早地发现和治疗。个体患者对手术干预的反应可能会更准确地预测，如果了解其特定的遗传病因，手术结果可能会得到改善。最后，了解CCS的遗传学可能会激发创新非手术疗法的实施。

DESCRIPTION (provided by applicant): Congenital strabismus is the pathological misalignment of the eyes associated with loss of binocular vision. It affects up to 4% of the population worldwide and 6-12 million people in the United States, and can reduce vision in one or both eyes, impair depth perception, and disturb interpersonal interactions and self-esteem. Congenital strabismus may be differentiated into comitant and incomitant forms. Incomitant forms account for 2% of cases, and affected individuals have limited eye movements such that the angle varies with gaze direction. Comitant congenital strabismus (CCS) accounts for 98% of cases, and affected individuals have full eye movements, with the angle of misalignment remaining constant with changes in gaze direction. It includes diagnoses such as esotropia, exotropia, and monofixation syndrome. Genetic and neurodevelopmental studies of rare forms of incomitant strabismus have revealed that it can result from mutations in genes critical to ocular cranial motor neuron development and to the proper growth and guidance of developing axons. In contrast, despite its high incidence, significant morbidity, and high cost to society in lost productivity, the underlying genetic contributors to CCS remain a mystery. Population, family-based, and twin studies all support a strong genetic contribution to CCS, with the relative risk to a first-degree relative of a proband estimated to be between 3 and 5. CCS is well suited for family-based analysis because of its early age of onset, high rate of family recurrence, and ease of family members' recruitment. Thus, the current proposal aims to utilize the existing infrastructure and multidisciplinary team to: (1) Expand ascertainment and phenotypic analysis of CCS for both clinical and genetic studies; (2) Acquire and curate genome-wide genotype data of CCS; (3) Identify rare genetic variants underlying CCS through genome-wide homozygosity mapping and linkage analysis; and (4) Identify common variants contributing to esotropia through genome-wide association study (GWAS). An improved understanding of the genetic etiologies of CCS should provide insight into its neuro-developmental basis and could have a profoundly positive impact on the health and well being of the population. Identification of patients or families at highest risk will improve the efficiency of screening programs, allowing for earlier detection and treatment. The response of individual patients to surgical intervention might be predicted with more accuracy and the surgical outcomes improved if their specific genetic etiology is understood. Finally, understanding the genetics of CCS may inspire the implementation of innovative nonsurgical therapies.