Genetic Etiologies of Horizontal Strabismus

水平斜视的遗传病因学

• 批准号: 8656114
• 负责人: Elizabeth C. Engle
• 金额: $ 42.63万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8656114
• 关键词: Accounting; Affect; African; Age of Onset; Asians; Axon; Binocular Vision; Candidate Disease Gene; Caucasians; Caucasoid Race; Cephalic; Childhood; Clinical; Clinical Research; Complex; DNA; Data; Depth Perception; Detection; Development; Diagnosis; Early Diagnosis; Early treatment; Enrollment; Esotropia; European; Exotropia; Eye; Eye Movements; Family; Family member; Feasibility Studies; First Degree Relative; Foundations; Funding; Future; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Grant; Growth; Health; Incidence; Individual; Interdisciplinary Study; Interpersonal Relations; Lead; Maps; Morbidity - disease rate; Mutation; Operative Surgical Procedures; Outcome; Participant; Patients; Phenotype; Population; Predisposition; Process; Productivity; Proteins; Quality Control; Recurrence; Relative Risks; Research Infrastructure; Sampling; Secondary to; Societies; Staging; Strabismus; Twin Studies; United States; Variant; Visual impairment; base; case control; clinical research site; cohort; cost; family structure; fitness; gaze; genetic linkage analysis; genetic pedigree; genetic variant; genome wide association study; genome-wide; high risk; improved; infancy; innovation; insight; member; monofixation syndrome; motor neuron development; multidisciplinary; proband; programs; public health relevance; rare variant; reproductive; response; scale up; screening; self esteem; success; trait; transcription factor

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.

描述（由申请人提供）：先天性斜视是与双眼视力丧失相关的病理性眼睛错位。它影响着全球多达 4% 的人口和美国 6-1200 万人，并会降低一只或双眼的视力，损害深度知觉，并扰乱人际交往和自尊。先天性斜视可分为伴随性斜视和非伴随性斜视。不相容形式占病例的 2%，受影响的个体眼球运动有限，因此角度随凝视方向而变化。共生性先天性斜视 (CCS) 占 98% 的病例，受影响的个体具有充分的眼球运动，随着注视方向的变化，错位角度保持恒定。它包括内斜视、外斜视和单注视综合征等诊断。对罕见形式的伴随性斜视的遗传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轴突发育的正常生长和引导至关重要的基因突变引起的。相比之下，尽管 CCS 发病率高、发病率高且生产力损失给社会造成高昂成本，但 CCS 的潜在遗传因素仍然是个谜。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 非常适合基于家庭的分析，因为其发病年龄早、家族复发率高、易于家族成员招募。因此，当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的确定和表型分析，用于临床和遗传学研究； (2) 获取和整理CCS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，识别CCS背后的罕见遗传变异； (4) 通过全基因组关联研究 (GWAS) 识别导致内斜视的常见变异。更好地了解 CCS 的遗传病因应该有助于深入了解其神经发育基础，并可能对人群的健康和福祉产生深远的积极影响。识别风险最高的患者或家庭将提高筛查计划的效率，从而实现早期发现和治疗。如果了解患者的具体遗传病因，则可以更准确地预测个体患者对手术干预的反应，并且手术结果会得到改善。最后，了解 CCS 的遗传学可能会激发创新非手术疗法的实施。