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
<p dir="ltr">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 wi...
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2020
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| _version_ | 1864513525921087488 |
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| author | Jonathan D. J. Labonne (18090841) |
| author2 | Terri M. Driessen (10870797) Marvin E. Harris (18090844) Il-Keun Kong (85884) Soumia Brakta (6020921) John Theisen (18090847) Modibo Sangare (18090850) Lawrence C. Layman (13913559) Cheol-Hee Kim (36752) Janghoo Lim (85014) Hyung-Goo Kim (728597) |
| author2_role | author author author author author author author author author author |
| author_facet | Jonathan D. J. Labonne (18090841) Terri M. Driessen (10870797) Marvin E. Harris (18090844) Il-Keun Kong (85884) Soumia Brakta (6020921) John Theisen (18090847) Modibo Sangare (18090850) Lawrence C. Layman (13913559) Cheol-Hee Kim (36752) Janghoo Lim (85014) Hyung-Goo Kim (728597) |
| author_role | author |
| dc.creator.none.fl_str_mv | Jonathan D. J. Labonne (18090841) Terri M. Driessen (10870797) Marvin E. Harris (18090844) Il-Keun Kong (85884) Soumia Brakta (6020921) John Theisen (18090847) Modibo Sangare (18090850) Lawrence C. Layman (13913559) Cheol-Hee Kim (36752) Janghoo Lim (85014) Hyung-Goo Kim (728597) |
| dc.date.none.fl_str_mv | 2020-01-19T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.3390/jcm9010274 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/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_31/25331218 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Neurosciences microdeletion LRRK2 autism HDHD1 PNPLA4 intellectual disability parkinsonism XLID 12q12 Xp22.31 |
| dc.title.none.fl_str_mv | 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 |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Clinical Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/jcm9010274" target="_blank">https://dx.doi.org/10.3390/jcm9010274</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_518dd4d2eae6848499e783d1a1ebcdd9 |
| identifier_str_mv | 10.3390/jcm9010274 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25331218 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31Jonathan D. J. Labonne (18090841)Terri M. Driessen (10870797)Marvin E. Harris (18090844)Il-Keun Kong (85884)Soumia Brakta (6020921)John Theisen (18090847)Modibo Sangare (18090850)Lawrence C. Layman (13913559)Cheol-Hee Kim (36752)Janghoo Lim (85014)Hyung-Goo Kim (728597)Biomedical and clinical sciencesClinical sciencesNeurosciencesmicrodeletionLRRK2autismHDHD1PNPLA4intellectual disabilityparkinsonismXLID12q12Xp22.31<p dir="ltr">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.</p><h2>Other Information</h2><p dir="ltr">Published in: Journal of Clinical Medicine<br>License: <a href="https://creativecommons.org/licenses/by/4.0/" target="_blank">https://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.3390/jcm9010274" target="_blank">https://dx.doi.org/10.3390/jcm9010274</a></p>2020-01-19T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.3390/jcm9010274https://figshare.com/articles/journal_contribution/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_31/25331218CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/253312182020-01-19T03:00:00Z |
| spellingShingle | 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 Jonathan D. J. Labonne (18090841) Biomedical and clinical sciences Clinical sciences Neurosciences microdeletion LRRK2 autism HDHD1 PNPLA4 intellectual disability parkinsonism XLID 12q12 Xp22.31 |
| status_str | publishedVersion |
| 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 | Biomedical and clinical sciences Clinical sciences Neurosciences microdeletion LRRK2 autism HDHD1 PNPLA4 intellectual disability parkinsonism XLID 12q12 Xp22.31 |