Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance
Abstract Background Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and...
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| Format: | Article |
| Language: | English |
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Wiley
2020-08-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.1336 |
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| author | Alice Traversa Enrica Marchionni Agnese Giovannetti Maria L. Genovesi Noemi Panzironi Katia Margiotti Giulia Napoli Francesca Piceci Sparascio Alessandro De Luca Francesco Petrizzelli Massimo Carella Francesco Cardona Silvia Bernardo Lucia Manganaro Tommaso Mazza Antonio Pizzuti Viviana Caputo |
| author_facet | Alice Traversa Enrica Marchionni Agnese Giovannetti Maria L. Genovesi Noemi Panzironi Katia Margiotti Giulia Napoli Francesca Piceci Sparascio Alessandro De Luca Francesco Petrizzelli Massimo Carella Francesco Cardona Silvia Bernardo Lucia Manganaro Tommaso Mazza Antonio Pizzuti Viviana Caputo |
| author_sort | Alice Traversa |
| collection | DOAJ |
| description | Abstract Background Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease‐causing. Methods A trio‐based clinical exome sequencing (CES) was performed. Results Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM_139058.3:c.922G>T; NP_620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild‐type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents. Conclusion This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS. |
| first_indexed | 2024-03-07T23:16:23Z |
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| id | doaj.art-dc2be2928238438d93f55dee99ed9483 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-03-07T23:16:23Z |
| publishDate | 2020-08-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-dc2be2928238438d93f55dee99ed94832024-02-21T11:08:50ZengWileyMolecular Genetics & Genomic Medicine2324-92692020-08-0188n/an/a10.1002/mgg3.1336Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritanceAlice Traversa0Enrica Marchionni1Agnese Giovannetti2Maria L. Genovesi3Noemi Panzironi4Katia Margiotti5Giulia Napoli6Francesca Piceci Sparascio7Alessandro De Luca8Francesco Petrizzelli9Massimo Carella10Francesco Cardona11Silvia Bernardo12Lucia Manganaro13Tommaso Mazza14Antonio Pizzuti15Viviana Caputo16Laboratory of Clinical Genomics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyLaboratory of Clinical Genomics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyLaboratorio di Genetica Medica ALTAMEDICA Rome ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyUOS Diagnosi Genetica Molecolare Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyLaboratory of Medical Genetics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) ItalyDepartment of Human Neurosciences Sapienza University of Rome Rome ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyDepartment of Radiological, Oncological, and Pathological Anatomy Sciences Sapienza University of Rome Rome ItalyLaboratory of Bioinformatics Fondazione IRCCS Casa Sollievo della Sofferenza San Giovanni Rotondo (FG) ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyDepartment of Experimental Medicine Sapienza University of Rome Rome ItalyAbstract Background Corpus callosum agenesis (ACC) is one of the most frequent Central Nervous System (CNS) malformations. However, genetics underlying isolated forms is still poorly recognized. Here, we report on two female familial cases with partial ACC. The proband shows isolated partial ACC and a mild neurodevelopmental phenotype. A fetus from a previous interrupted pregnancy exhibited a complex phenotype including partial ACC and the occurrence of a de novo 17q12 microduplication, which was interpreted as probably disease‐causing. Methods A trio‐based clinical exome sequencing (CES) was performed. Results Clinical exome sequencing data analysis led to identifying a heterozygous nonsense variant (NM_139058.3:c.922G>T; NP_620689.1:p.Glu308Ter) in the aristaless related homeobox gene (ARX) in the proband, with a putative de novo occurrence, producing a hypothetical protein lacking two essential domains. Sanger analysis confirmed the wild‐type status of both parents in different tissues, and disclosed the occurrence of the nonsense variant in the fetus of the interrupted pregnancy, suggesting a formerly unrecognized contribution of the ARX mutation to the fetus' phenotype and gonadal or gonadosomatic mosaicism in one of the parents. Conclusion This study describes the phenotype associated with a heterozygous loss of function variant in ARX. Moreover, it highlights the importance of investigating both chromosomal and genetic contributions in cases of complex syndromic phenotypes involving CNS.https://doi.org/10.1002/mgg3.133617q12 duplication syndromearray‐CGHARXclinical exome sequencingcorpus callosumdual diagnosis |
| spellingShingle | Alice Traversa Enrica Marchionni Agnese Giovannetti Maria L. Genovesi Noemi Panzironi Katia Margiotti Giulia Napoli Francesca Piceci Sparascio Alessandro De Luca Francesco Petrizzelli Massimo Carella Francesco Cardona Silvia Bernardo Lucia Manganaro Tommaso Mazza Antonio Pizzuti Viviana Caputo Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance Molecular Genetics & Genomic Medicine 17q12 duplication syndrome array‐CGH ARX clinical exome sequencing corpus callosum dual diagnosis |
| title | Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance |
| title_full | Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance |
| title_fullStr | Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance |
| title_full_unstemmed | Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance |
| title_short | Heterozygous nonsense ARX mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co‐inheritance |
| title_sort | heterozygous nonsense arx mutation in a family highlights the complexity of clinical and molecular diagnosis in case of chromosomal and single gene disorder co inheritance |
| topic | 17q12 duplication syndrome array‐CGH ARX clinical exome sequencing corpus callosum dual diagnosis |
| url | https://doi.org/10.1002/mgg3.1336 |
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