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Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31
We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small infor...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019335/ https://www.ncbi.nlm.nih.gov/pubmed/31963867 http://dx.doi.org/10.3390/jcm9010274 |
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author | Labonne, Jonathan D. J. Driessen, Terri M. Harris, Marvin E. Kong, Il-Keun Brakta, Soumia Theisen, John Sangare, Modibo Layman, Lawrence C. Kim, Cheol-Hee Lim, Janghoo Kim, Hyung-Goo |
author_facet | Labonne, Jonathan D. J. Driessen, Terri M. Harris, Marvin E. Kong, Il-Keun Brakta, Soumia Theisen, John Sangare, Modibo Layman, Lawrence C. Kim, Cheol-Hee Lim, Janghoo Kim, Hyung-Goo |
author_sort | Labonne, Jonathan D. J. |
collection | PubMed |
description | We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning. |
format | Online Article Text |
id | pubmed-7019335 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70193352020-03-09 Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 Labonne, Jonathan D. J. Driessen, Terri M. Harris, Marvin E. Kong, Il-Keun Brakta, Soumia Theisen, John Sangare, Modibo Layman, Lawrence C. Kim, Cheol-Hee Lim, Janghoo Kim, Hyung-Goo J Clin Med Article We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning. MDPI 2020-01-19 /pmc/articles/PMC7019335/ /pubmed/31963867 http://dx.doi.org/10.3390/jcm9010274 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Labonne, Jonathan D. J. Driessen, Terri M. Harris, Marvin E. Kong, Il-Keun Brakta, Soumia Theisen, John Sangare, Modibo Layman, Lawrence C. Kim, Cheol-Hee Lim, Janghoo Kim, Hyung-Goo Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title_full | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title_fullStr | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title_full_unstemmed | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title_short | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31 |
title_sort | comparative genomic mapping implicates lrrk2 for intellectual disability and autism at 12q12, and hdhd1, as well as pnpla4, for x-linked intellectual disability at xp22.31 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7019335/ https://www.ncbi.nlm.nih.gov/pubmed/31963867 http://dx.doi.org/10.3390/jcm9010274 |
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