A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis
DICER1 syndrome is an autosomal-dominant disorder that results in malignant or benign tumors. A number of distinct pathogenic germline and somatic variants have been identified as causing multinodular goiter (MNG). The purpose of the present study was to identify and characterize the genetic cause u...
| Autores principales: | , , , , , , , , |
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| Formato: | info:ar-repo/semantics/artículo |
| Lenguaje: | Inglés |
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Springer
2025
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| Acceso en línea: | http://hdl.handle.net/20.500.12123/21729 https://link.springer.com/article/10.1007/s12020-024-04098-3 https://doi.org/10.1007/s12020-024-04098-3 |
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| author | Targovnik, Héctor M. Barh, Debmalya Papendieck, Patricia Adrover, Ezequiela Gallo, Ariel M. Chiesa, Ana Marques Da Silva, Wanderson Azevedo, Vasco Rivolta, Carina M. |
| author_browse | Adrover, Ezequiela Azevedo, Vasco Barh, Debmalya Chiesa, Ana Gallo, Ariel M. Marques Da Silva, Wanderson Papendieck, Patricia Rivolta, Carina M. Targovnik, Héctor M. |
| author_facet | Targovnik, Héctor M. Barh, Debmalya Papendieck, Patricia Adrover, Ezequiela Gallo, Ariel M. Chiesa, Ana Marques Da Silva, Wanderson Azevedo, Vasco Rivolta, Carina M. |
| author_sort | Targovnik, Héctor M. |
| collection | INTA Digital |
| description | DICER1 syndrome is an autosomal-dominant disorder that results in malignant or benign tumors. A number of distinct pathogenic germline and somatic variants have been identified as causing multinodular goiter (MNG). The purpose of the present study was to identify and characterize the genetic cause underlying the familial form of MNG through a whole-exome sequencing (WES) analysis in an Argentine family with three affected siblings. Clinical, biochemical and molecular genetics as well as bioinformatics analysis were performed. A novel heterozygous variant in the DICER1 gene was identified in the proband patient by WES. The variant was a single guanine deletion at nucleotide position 2,042 (NM_177438.3:c.2042del) resulting in a frameshift at amino acid 681 with a putative premature stop codon [NP_803187.1:p.Gly681ValfsTer4]. Family segregation analysis showed that his affected sister and his affected brother also were heterozygous for same variant, whereas the father was a healthy heterozygous carrier of the variant and the healthy mother harbor only wild-type alleles in the DICER1 gene. We have also observed that the frameshift variant does not interfere with the pre-mRNA splicing of the exon 13. In addition, two clinically relevant heterozygous variants, not associated with thyroid disease, were also identified in index sibling using the Franklin platform, a frameshift [NP_000234.1:p.Thr55AsnfsTer49] in the MEFV gene (familial mediterranean fever) and a missense [NP_004530.1:p.Ala422Thr] in the NARS1 gene (neurodevelopmental delay and ataxia). In conclusion, in the present study we have identified a novel frameshift variant corresponding to NP_803187.1:p.Gly681ValfsTer4 in the DUF 283 domain of DICER1. The results were in accordance with previous observations confirming the genetic heterogeneity of DICER1 syndrome. Moreover, the identification of this variant in the unaffected father substantiates the hypothesis of incomplete/reduced penetrance. |
| format | info:ar-repo/semantics/artículo |
| id | INTA21729 |
| institution | Instituto Nacional de Tecnología Agropecuaria (INTA -Argentina) |
| language | Inglés |
| publishDate | 2025 |
| publishDateRange | 2025 |
| publishDateSort | 2025 |
| publisher | Springer |
| publisherStr | Springer |
| record_format | dspace |
| spelling | INTA217292025-03-19T13:14:56Z A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis Targovnik, Héctor M. Barh, Debmalya Papendieck, Patricia Adrover, Ezequiela Gallo, Ariel M. Chiesa, Ana Marques Da Silva, Wanderson Azevedo, Vasco Rivolta, Carina M. Bocio Genética Análisis de Secuencias Bioinformática Goitre Genetics Sequence Analysis Bioinformatics DICER1 syndrome is an autosomal-dominant disorder that results in malignant or benign tumors. A number of distinct pathogenic germline and somatic variants have been identified as causing multinodular goiter (MNG). The purpose of the present study was to identify and characterize the genetic cause underlying the familial form of MNG through a whole-exome sequencing (WES) analysis in an Argentine family with three affected siblings. Clinical, biochemical and molecular genetics as well as bioinformatics analysis were performed. A novel heterozygous variant in the DICER1 gene was identified in the proband patient by WES. The variant was a single guanine deletion at nucleotide position 2,042 (NM_177438.3:c.2042del) resulting in a frameshift at amino acid 681 with a putative premature stop codon [NP_803187.1:p.Gly681ValfsTer4]. Family segregation analysis showed that his affected sister and his affected brother also were heterozygous for same variant, whereas the father was a healthy heterozygous carrier of the variant and the healthy mother harbor only wild-type alleles in the DICER1 gene. We have also observed that the frameshift variant does not interfere with the pre-mRNA splicing of the exon 13. In addition, two clinically relevant heterozygous variants, not associated with thyroid disease, were also identified in index sibling using the Franklin platform, a frameshift [NP_000234.1:p.Thr55AsnfsTer49] in the MEFV gene (familial mediterranean fever) and a missense [NP_004530.1:p.Ala422Thr] in the NARS1 gene (neurodevelopmental delay and ataxia). In conclusion, in the present study we have identified a novel frameshift variant corresponding to NP_803187.1:p.Gly681ValfsTer4 in the DUF 283 domain of DICER1. The results were in accordance with previous observations confirming the genetic heterogeneity of DICER1 syndrome. Moreover, the identification of this variant in the unaffected father substantiates the hypothesis of incomplete/reduced penetrance. Instituto de Biotecnología Fil: Targovnik, Héctor M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética. Cátedra de Genética; Argentina Fil: Barh, Debmalya. Federal University of Minas Gerais. Department of Genetics, Ecology & Evolution. Institute of Biological Sciences; Brasil Fil: Barh, Debmalya. Institute of Integrative Omics & Applied Biotechnology; India Fil: Papendieck, Patricia. Hospital de Niños “Ricardo Gutiérrez”. Centro de Investigaciones Endocrinológicas; Argentina Fil: Papendieck, Patricia. Consejo Nacional de Investigaciones Científicas y Técnicas. División Endocrinología. Centro de Investigaciones Endocrinológicas; Argentina Fil: Adrover, Ezequiela. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética. Cátedra de Genética; Argentina Fil: Adrover, Ezequiela. Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina Fil: Adrover, Ezequiela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina Fil: Gallo, Ariel M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética. Cátedra de Genética; Argentina Fil: Gallo, Ariel M. Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina Fil: Gallo, Ariel M. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina Fil: Chiesa, Ana. Hospital de Niños “Ricardo Gutiérrez”. Centro de Investigaciones Endocrinológicas; Argentina Fil: Chiesa, Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. División Endocrinología. Centro de Investigaciones Endocrinológicas; Argentina Fil: Marques Da Silva, Wanderson. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina Fil: Marques Da Silva, Wanderson. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Azevedo, Vasco. Federal University of Minas Gerais. Department of Genetics, Ecology & Evolution. Institute of Biological Sciences; Brasil Fil: Rivolta, Carina M. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología, Biotecnología y Genética. Cátedra de Genética; Argentina Fil: Rivolta, Carina M. Universidad de Buenos Aires. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina Fil: Rivolta, Carina M. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Inmunología, Genética y Metabolismo (INIGEM); Argentina 2025-03-19T13:11:09Z 2025-03-19T13:11:09Z 2025-03 info:ar-repo/semantics/artículo info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://hdl.handle.net/20.500.12123/21729 https://link.springer.com/article/10.1007/s12020-024-04098-3 1559-0100 https://doi.org/10.1007/s12020-024-04098-3 eng info:eu-repo/semantics/restrictedAccess http://creativecommons.org/licenses/by-nc-sa/4.0/ Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) application/pdf Springer Endocrine 87 (3) : 1150-1161. (March 2025) |
| spellingShingle | Bocio Genética Análisis de Secuencias Bioinformática Goitre Genetics Sequence Analysis Bioinformatics Targovnik, Héctor M. Barh, Debmalya Papendieck, Patricia Adrover, Ezequiela Gallo, Ariel M. Chiesa, Ana Marques Da Silva, Wanderson Azevedo, Vasco Rivolta, Carina M. A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title | A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title_full | A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title_fullStr | A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title_full_unstemmed | A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title_short | A novel pathogenic DICER1 gene variant is associated with hereditary multinodular goiter in an Argentine family as evidenced by clinical, biochemical and molecular genetic analysis |
| title_sort | novel pathogenic dicer1 gene variant is associated with hereditary multinodular goiter in an argentine family as evidenced by clinical biochemical and molecular genetic analysis |
| topic | Bocio Genética Análisis de Secuencias Bioinformática Goitre Genetics Sequence Analysis Bioinformatics |
| url | http://hdl.handle.net/20.500.12123/21729 https://link.springer.com/article/10.1007/s12020-024-04098-3 https://doi.org/10.1007/s12020-024-04098-3 |
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