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Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder

Yahia, Ashraf LU orcid ; Li, Danyang ; Lejerkrans, Sanna ; Rajagopalan, Shyam ; Kalnak, Nelli LU and Tammimies, Kristiina (2024) In Human Genetics 143(2). p.169-183
Abstract

Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the... (More)

Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.

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author
; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
in
Human Genetics
volume
143
issue
2
pages
169 - 183
publisher
Springer
external identifiers
  • pmid:38300321
  • scopus:85183858277
ISSN
0340-6717
DOI
10.1007/s00439-023-02636-z
language
English
LU publication?
no
additional info
Publisher Copyright: © The Author(s) 2024.
id
6f8fa70b-4e31-4cac-838d-429f1656317d
date added to LUP
2026-06-05 10:32:06
date last changed
2026-06-06 03:34:12
@article{6f8fa70b-4e31-4cac-838d-429f1656317d,
  abstract     = {{<p>Developmental language disorder (DLD) overlaps clinically, genetically, and pathologically with other neurodevelopmental disorders (NDD), corroborating the concept of the NDD continuum. There is a lack of studies to understand the whole genetic spectrum in individuals with DLD. Previously, we recruited 61 probands with severe DLD from 59 families and examined 59 of them and their families using microarray genotyping with a 6.8% diagnostic yield. Herein, we investigated 53 of those probands using whole exome sequencing (WES). Additionally, we used polygenic risk scores (PRS) to understand the within family enrichment of neurodevelopmental difficulties and examine the associations between the results of language-related tests in the probands and language-related PRS. We identified clinically significant variants in four probands, resulting in a 7.5% (4/53) molecular diagnostic yield. Those variants were in PAK2, MED13, PLCB4, and TNRC6B. We also prioritized additional variants for future studies for their role in DLD, including high-impact variants in PARD3 and DIP2C. PRS did not explain the aggregation of neurodevelopmental difficulties in these families. We did not detect significant associations between the language-related tests and language-related PRS. Our results support using WES as the first-tier genetic test for DLD as it can identify monogenic DLD forms. Large-scale sequencing studies for DLD are needed to identify new genes and investigate the polygenic contribution to the condition.</p>}},
  author       = {{Yahia, Ashraf and Li, Danyang and Lejerkrans, Sanna and Rajagopalan, Shyam and Kalnak, Nelli and Tammimies, Kristiina}},
  issn         = {{0340-6717}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{169--183}},
  publisher    = {{Springer}},
  series       = {{Human Genetics}},
  title        = {{Whole exome sequencing and polygenic assessment of a Swedish cohort with severe developmental language disorder}},
  url          = {{http://dx.doi.org/10.1007/s00439-023-02636-z}},
  doi          = {{10.1007/s00439-023-02636-z}},
  volume       = {{143}},
  year         = {{2024}},
}