A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q
A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q
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DOI：
10.1024/1422-4917/a000758
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发表时间：
2020-11-01
影响因子：
1.2
通讯作者：
Kuss, Andreas W.
中科院分区：
文献类型：
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作者：
Grimm, Tiemo;Garshasbi, Masoud;Kuss, Andreas W.
目的：发展性阅读障碍是一种高度遗传的特定阅读和写作障碍。为了确定这种残疾的可能新位点和候选基因，我们研究了一个四代谱系，其中阅读障碍的传播与常染色体显性遗传模式一致。方法：我们对来自一名受影响的家庭成员和一名未受影响的家庭成员的 DNA 中与阅读障碍共分离的单倍型内的蛋白质编码外显子、外显子-内含子边界和保守的基因外区域进行了基于全基因组芯片的 SNP 基因分型和参数连锁分析和测序分析。通过对所有可用的家庭成员进行测序来确认共隔离。此外，我们还分析了 96 名患有阅读障碍的个体，他们之前在染色体 4q28 上显示出阳性 LOD 评分，并且还分析了更大的样本 (n = 2591)。结果：我们在染色体 4q 上发现了一个显着的连锁间隔，序列分析显示，在与阅读障碍共分离的阅读障碍家族成员中，大脑 3' UTR 中表达 SPRY1 存在核苷酸变异。这种序列改变可能会影响 IGF2BP1 RNA 结合蛋白的结合效率，从而影响 SPRY1 基因产物的表达水平。对诵读困难人群中的 96 名个体进行的分析揭示了该基因的第二个杂合变异，而先证者未受影响的姐妹中不存在该变异。对该地区更大样本的调查进一步发现，邻近 SNV 的 2,591 个人的言语短期记忆（数字跨度）的名义 p 值为 0.0016。在校正分析的 SNV 的局部数量并考虑连锁不平衡后，我们发现这对应于该表型的 p 值为 0.0678。结论：我们描述了家族性阅读障碍的一个新位点，并讨论了 SPRY1 可能在单基因形式阅读障碍的病因学中发挥作用的可能性。
Objective: Developmental dyslexia is a highly heritable specific reading and writing disability. To identify a possible new locus and candidate gene for this disability, we investigated a four-generation pedigree where transmission of dyslexia is consistent with an autosomal dominant inheritance pattern. Methods: We performed genome wide array-based SNP genotyping and parametric linkage analysis and sequencing analysis of protein-coding exons, exon-intron boundaries and conserved extragenic regions within the haplotype cosegregating with dyslexia in DNA from one affected and one unaffected family member. Cosegregation was confirmed by sequencing all available family members. Additionally, we analyzed 96 dyslexic individuals who had previously shown positive LOD scores on chromosome 4q28 as well as an even larger sample (n = 2591). Results: We found a single prominent linkage interval on chromosome 4q, where sequence analysis revealed a nucleotide variant in the 3' UTR of brain expressed SPRY1 in the dyslexic family member that cosegregated with dyslexia. This sequence alteration might affect the binding efficiency of the IGF2BP1 RNA-binding protein and thus influence the expression level of the SPRY1 gene product. An analysis of 96 individuals from a cohort of dyslexic individuals revealed a second heterozygous variant in this gene, which was absent in the unaffected sister of the proband. An investigation of the region in a much larger sample further found a nominal p-value of 0.0016 for verbal short-term memory (digit span) in 2,591 individuals for a neighboring SNV. After correcting for the local number of analyzed SNVs, and after taking into account linkage disequilibrium, we found this corresponds to a p-value of 0.0678 for this phenotype. Conclusions: We describe a new locus for familial dyslexia and discuss the possibility that SPRY1 might play a role in the etiology of a monogenic form of dyslexia.