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  A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q

Grimm, T., Garshasbi, M., Puettmann, L., Chen, W., Ullmann, R., Müller-Myhsok, B., et al. (2020). A Novel Locus and Candidate Gene for Familial Developmental Dyslexia on Chromosome 4q. Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie, 48(6), 478-489. doi:10.1024/1422-4917/a000758.

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Grimm_2020.pdf (Publisher version), 419KB
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© 2020 Hogrefe
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 Creators:
Grimm, Tiemo , Author
Garshasbi, Masoud, Author
Puettmann, Lucia, Author
Chen, Wei, Author
Ullmann, Reinhard, Author
Müller-Myhsok, Bertram , Author
Klopocki, Eva, Author
Herbst, Lina, Author
Haug, Janina , Author
Jensen, Lars R. , Author
Fischer, Christine , Author
Nöthen, Markus , Author
Ludwig, Kerstin , Author
Warnke, Andreas , Author
Ott, Jürg, Author
Schulte-Körne, Gerd, Author
Ropers, Hans-Hilger1, Author              
Kuss, Andreas W. , Author
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              

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Free keywords: developmental dyslexia, linkage analysis, next generation sequencing, SPRY1, genetic variants
 Abstract: 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.

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Language(s): eng - English
 Dates: 2020-11-01
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1024/1422-4917/a000758
PMID: 33172359
 Degree: -

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Title: Zeitschrift fur Kinder- und Jugendpsychiatrie und Psychotherapie
Source Genre: Journal
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Publ. Info: Göttingen : Hogrefe
Pages: 12 Volume / Issue: 48 (6) Sequence Number: - Start / End Page: 478 - 489 Identifier: ISSN: 1422-4917 (print) 1664-2880 (online)