Genetic Etiologies of Horizontal Strabismus

描述(申请人提供)：先天性斜视是与双眼视觉丧失有关的眼睛的病理性错位。它影响着全球高达4%的人口和美国的600万至1200万人，并会降低一只或两只眼睛的视力，损害深度知觉，并扰乱人际交往和自尊。先天性斜视可分为共同性斜视和非共同性斜视。伴发形式占病例的2%，受影响的个人眼球运动有限，角度随凝视方向变化。共同性先天性斜视(CCS)占98%的病例，受影响的个体有充分的眼球运动，错位角度保持不变，随着凝视方向的变化。它包括诸如内斜视、外斜视和单注视综合征的诊断。对罕见形式的共同性斜视的遗传学和神经发育研究表明，这种斜视可能是由于对眼颅运动神经元发育以及对发育中的轴突的正常生长和引导至关重要的基因突变所致。相比之下，尽管CCS的发病率高，发病率高，生产力丧失给社会带来了高昂的成本，但CCS的潜在遗传因素仍然是一个谜。人群、基于家庭和双胞胎的研究都支持CCS的强大遗传贡献，先证者的一级亲属的相对风险估计在3到5之间。CCS非常适合于基于家庭的分析，因为它起病年龄早，家庭复发率高，易于招募家庭成员。因此，目前的建议旨在利用现有的基础设施和多学科团队来：(1)扩大CCS的确定和表型分析，用于临床和遗传学研究；(2)获取和管理CCS的全基因组基因数据；(3)通过全基因组纯合性作图和连锁分析，识别隐藏在CCS背后的罕见遗传变异；以及(4)通过全基因组关联研究(Gwas)，识别导致内斜视的常见变异。对CCS遗传病因的更好理解应该有助于洞察其神经发育基础，并可能对人群的健康和福祉产生深远的积极影响。识别最高风险的患者或家属将提高筛查计划的效率，从而能够更早地发现和治疗。如果了解患者的特定遗传病因，个体患者对手术干预的反应可能会更准确地预测，手术结果也会得到改善。最后，了解CCS的遗传学可能会激励创新的非手术治疗的实施。

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.