A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome
<p dir="ltr">In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)<i>dn</i>, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deleti...
Saved in:
| Main Author: | |
|---|---|
| Other Authors: | , , , , , , , , , , , , , , , , , |
| Published: |
2023
|
| Subjects: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1864513507065593856 |
|---|---|
| author | Afif Ben-Mahmoud (13913550) |
| author2 | Shotaro Kishikawa (19483132) Vijay Gupta (209146) Natalia T. Leach (19483135) Yiping Shen (102565) Oana Moldovan (808331) Himanshu Goel (509740) Bruce Hopper (19483138) Kara Ranguin (19483141) Nicolas Gruchy (14829754) Saskia M Maas (19483144) Yves Lacassie (6034238) Soo-Hyun Kim (10655) Woo-Yang Kim (206701) Bradley J. Quade (19483147) Cynthia C. Morton (10860072) Cheol-Hee Kim (36752) Lawrence C. Layman (13913559) Hyung-Goo Kim (728597) |
| author2_role | author author author author author author author author author author author author author author author author author author |
| author_facet | Afif Ben-Mahmoud (13913550) Shotaro Kishikawa (19483132) Vijay Gupta (209146) Natalia T. Leach (19483135) Yiping Shen (102565) Oana Moldovan (808331) Himanshu Goel (509740) Bruce Hopper (19483138) Kara Ranguin (19483141) Nicolas Gruchy (14829754) Saskia M Maas (19483144) Yves Lacassie (6034238) Soo-Hyun Kim (10655) Woo-Yang Kim (206701) Bradley J. Quade (19483147) Cynthia C. Morton (10860072) Cheol-Hee Kim (36752) Lawrence C. Layman (13913559) Hyung-Goo Kim (728597) |
| author_role | author |
| dc.creator.none.fl_str_mv | Afif Ben-Mahmoud (13913550) Shotaro Kishikawa (19483132) Vijay Gupta (209146) Natalia T. Leach (19483135) Yiping Shen (102565) Oana Moldovan (808331) Himanshu Goel (509740) Bruce Hopper (19483138) Kara Ranguin (19483141) Nicolas Gruchy (14829754) Saskia M Maas (19483144) Yves Lacassie (6034238) Soo-Hyun Kim (10655) Woo-Yang Kim (206701) Bradley J. Quade (19483147) Cynthia C. Morton (10860072) Cheol-Hee Kim (36752) Lawrence C. Layman (13913559) Hyung-Goo Kim (728597) |
| dc.date.none.fl_str_mv | 2023-08-10T09:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-023-40037-4 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/A_cryptic_microdeletion_del_12_p11_21p11_23_within_an_unbalanced_translocation_t_7_12_q21_13_q23_1_implicates_new_candidate_loci_for_intellectual_disability_and_Kallmann_syndrome/26830957 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Kallmann Syndrome (KS) Intellectual Disability (ID) Chromosomal Deletion Candidate Genes Phenotypic-Genotypic Comparison Gene Expression TSPAN11 |
| dc.title.none.fl_str_mv | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)<i>dn</i>, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: <i>TSPAN11</i> as a potential KS candidate gene, <i>TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B</i>, and <i>ETFBKMT</i> as candidate genes for the neurodevelopmental disorder, and <i>INTS13, REP15, PPFIBP1</i>, and <i>FAR2</i> as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<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/10.1038/s41598-023-40037-4" target="_blank">https://dx.doi.org/10.1038/s41598-023-40037-4</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_9565978c67807d32d775f6514d24797b |
| identifier_str_mv | 10.1038/s41598-023-40037-4 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26830957 |
| publishDate | 2023 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndromeAfif Ben-Mahmoud (13913550)Shotaro Kishikawa (19483132)Vijay Gupta (209146)Natalia T. Leach (19483135)Yiping Shen (102565)Oana Moldovan (808331)Himanshu Goel (509740)Bruce Hopper (19483138)Kara Ranguin (19483141)Nicolas Gruchy (14829754)Saskia M Maas (19483144)Yves Lacassie (6034238)Soo-Hyun Kim (10655)Woo-Yang Kim (206701)Bradley J. Quade (19483147)Cynthia C. Morton (10860072)Cheol-Hee Kim (36752)Lawrence C. Layman (13913559)Hyung-Goo Kim (728597)Biological sciencesGeneticsBiomedical and clinical sciencesClinical sciencesKallmann Syndrome (KS)Intellectual Disability (ID)Chromosomal DeletionCandidate GenesPhenotypic-Genotypic ComparisonGene ExpressionTSPAN11<p dir="ltr">In a patient diagnosed with both Kallmann syndrome (KS) and intellectual disability (ID), who carried an apparently balanced translocation t(7;12)(q22;q24)<i>dn</i>, array comparative genomic hybridization (aCGH) disclosed a cryptic heterozygous 4.7 Mb deletion del(12)(p11.21p11.23), unrelated to the translocation breakpoint. This novel discovery prompted us to consider the possibility that the combination of KS and neurological disorder in this patient could be attributed to gene(s) within this specific deletion at 12p11.21-12p11.23, rather than disrupted or dysregulated genes at the translocation breakpoints. To further support this hypothesis, we expanded our study by screening five candidate genes at both breakpoints of the chromosomal translocation in a cohort of 48 KS patients. However, no mutations were found, thus reinforcing our supposition. In order to delve deeper into the characterization of the 12p11.21-12p11.23 region, we enlisted six additional patients with small copy number variations (CNVs) and analyzed eight individuals carrying small CNVs in this region from the DECIPHER database. Our investigation utilized a combination of complementary approaches. Firstly, we conducted a comprehensive phenotypic-genotypic comparison of reported CNV cases. Additionally, we reviewed knockout animal models that exhibit phenotypic similarities to human conditions. Moreover, we analyzed reported variants in candidate genes and explored their association with corresponding phenotypes. Lastly, we examined the interacting genes associated with these phenotypes to gain further insights. As a result, we identified a dozen candidate genes: <i>TSPAN11</i> as a potential KS candidate gene, <i>TM7SF3, STK38L, ARNTL2, ERGIC2, TMTC1, DENND5B</i>, and <i>ETFBKMT</i> as candidate genes for the neurodevelopmental disorder, and <i>INTS13, REP15, PPFIBP1</i>, and <i>FAR2</i> as candidate genes for KS with ID. Notably, the high-level expression pattern of these genes in relevant human tissues further supported their candidacy. Based on our findings, we propose that dosage alterations of these candidate genes may contribute to sexual and/or cognitive impairments observed in patients with KS and/or ID. However, the confirmation of their causal roles necessitates further identification of point mutations in these candidate genes through next-generation sequencing.</p><h2>Other Information</h2><p dir="ltr">Published in: Scientific Reports<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/10.1038/s41598-023-40037-4" target="_blank">https://dx.doi.org/10.1038/s41598-023-40037-4</a></p>2023-08-10T09:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-023-40037-4https://figshare.com/articles/journal_contribution/A_cryptic_microdeletion_del_12_p11_21p11_23_within_an_unbalanced_translocation_t_7_12_q21_13_q23_1_implicates_new_candidate_loci_for_intellectual_disability_and_Kallmann_syndrome/26830957CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/268309572023-08-10T09:00:00Z |
| spellingShingle | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome Afif Ben-Mahmoud (13913550) Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Kallmann Syndrome (KS) Intellectual Disability (ID) Chromosomal Deletion Candidate Genes Phenotypic-Genotypic Comparison Gene Expression TSPAN11 |
| status_str | publishedVersion |
| title | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| title_full | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| title_fullStr | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| title_full_unstemmed | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| title_short | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| title_sort | A cryptic microdeletion del(12)(p11.21p11.23) within an unbalanced translocation t(7;12)(q21.13;q23.1) implicates new candidate loci for intellectual disability and Kallmann syndrome |
| topic | Biological sciences Genetics Biomedical and clinical sciences Clinical sciences Kallmann Syndrome (KS) Intellectual Disability (ID) Chromosomal Deletion Candidate Genes Phenotypic-Genotypic Comparison Gene Expression TSPAN11 |