Strabismus is a common condition, affecting 1-4% of individuals. Isolated strabismus has been studied in families with Mendelian inheritance patterns. Despite the identification of multiple loci via linkage analyses, no specific genes have been identified from these studies. The current study is based on a seven-generation family with isolated strabismus inherited in an autosomal dominant manner. A total of 13 individuals from a common ancestor have been included for linkage analysis, and a single linkage signal has been identified at chromosome 14q12 with a multipoint LOD score of 4.69. Disruption of this locus is known to cause FOXG1 syndrome (or congenital Rett syndrome; OMIM #613454 and *164874), in which 84% of affected individuals present with strabismus. With the incorporation of next generation sequencing and in-depth bioinformatic analyses, a 4bp non-coding deletion was prioritized as the top candidate for the observed strabismus phenotype. The deletion is predicted to disrupt regulation of FOXG1, which encodes a transcription factor of the Forkhead family. Suggestive of an auto-regulation effect, the disrupted sequence matches the consensus FOXG1 and Forkhead family transcription factor binding site and has been observed in previous ChIP-seq studies to be bound by Foxg1 in early mouse brain development. The findings of this study indicate that the strabismus phenotype commonly observed within FOXG1 syndrome is separable from the more severe syndromic characteristics. Future study of this specific deletion may shed light on the regulation of FOXG1 expression and may enhance our understanding of the mechanisms contributing to strabismus and FOXG1 syndrome.

中文翻译：

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连锁分析确定14q12与FOXG1综合征区域重叠的孤立斜视基因座

斜视是一种常见疾病，会影响1-4％的个体。在具有孟德尔遗传模式的家庭中研究了孤立的斜视。尽管通过连锁分析鉴定了多个基因座，但从这些研究中尚未鉴定出特定基因。当前的研究基于一个以常染色体显性遗传的孤立斜视的七代家族。共有13位来自同一祖先的个体被用于连锁分析，并且在14q12染色体上鉴定出单连锁信号，其多点LOD得分为4.69。破坏该基因座可导致FOXG1综合征（或先天性Rett综合征； OMIM＃613454和* 164874），其中84％的患病者患有斜视。通过结合下一代测序和深入的生物信息学分析，将4bp非编码缺失作为观察斜视表型的首选。预计该缺失会破坏FOXG1的调控，该基因编码Forkhead家族的转录因子。暗示了自动调节作用，该破坏的序列与共有的FOXG1和Forkhead家族转录因子结合位点匹配，并且在先前的ChIP-seq研究中已观察到在小鼠早期大脑发育中被Foxg1结合。这项研究的发现表明，在FOXG1综合征内通常观察到的斜视表型与更严重的综合征特征是可分离的。