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Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum
BACKGROUND: We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample of 509 unrelated adults with type 2 diabetes and 459 controls, all belonging...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247206/ https://www.ncbi.nlm.nih.gov/pubmed/34193236 http://dx.doi.org/10.1186/s13023-021-01924-z |
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author | Mendoza-Caamal, Elvia C. Barajas-Olmos, Francisco Mirzaeicheshmeh, Elaheh Ilizaliturri-Flores, Ian Aguilar-Salinas, Carlos A. Gómez-Velasco, Donaji V. Cicerón-Arellano, Isabel Reséndiz-Rodríguez, Adriana Martínez-Hernández, Angélica Contreras-Cubas, Cecilia Islas-Andrade, Sergio Zerrweck, Carlos García-Ortiz, Humberto Orozco, Lorena |
author_facet | Mendoza-Caamal, Elvia C. Barajas-Olmos, Francisco Mirzaeicheshmeh, Elaheh Ilizaliturri-Flores, Ian Aguilar-Salinas, Carlos A. Gómez-Velasco, Donaji V. Cicerón-Arellano, Isabel Reséndiz-Rodríguez, Adriana Martínez-Hernández, Angélica Contreras-Cubas, Cecilia Islas-Andrade, Sergio Zerrweck, Carlos García-Ortiz, Humberto Orozco, Lorena |
author_sort | Mendoza-Caamal, Elvia C. |
collection | PubMed |
description | BACKGROUND: We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample of 509 unrelated adults with type 2 diabetes and 459 controls, all belonging to the DMS1 SIGMA-cohort (ExAC). We performed in silico analysis on missense variants using Variant Effect Predictor software. To evaluate co-segregation, predicted pathogenic variants were genotyped in other family members. We performed molecular dynamics analysis for the co-segregating variants. RESULTS: After filtering, Mendelian genotypes were confirmed in two probands bearing two novel variants, p.Arg252His and p.Lys68Gln. Both variants co-segregated with the AOMS3 phenotype in classic dominant autosomal inheritance with full penetrance. In silico analysis revealed impairment of the DYRK1B protein function by both variants. For the first time, we describe age-dependent variable expressivity of this entity, with central obesity and insulin resistance apparent in childhood; morbid obesity, severe hypertriglyceridemia, and labile type 2 diabetes appearing before 40 years of age; and hypertension emerging in the fifth decade of life. We also report the two youngest individuals suffering from AOMS3. CONCLUSIONS: Monogenic forms of metabolic diseases could be misdiagnosed and should be suspected in families with several affected members and early-onset metabolic phenotypes that are difficult to control. Early diagnostic strategies and medical interventions, even before symptoms or complications appear, could be useful. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-021-01924-z. |
format | Online Article Text |
id | pubmed-8247206 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-82472062021-07-06 Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum Mendoza-Caamal, Elvia C. Barajas-Olmos, Francisco Mirzaeicheshmeh, Elaheh Ilizaliturri-Flores, Ian Aguilar-Salinas, Carlos A. Gómez-Velasco, Donaji V. Cicerón-Arellano, Isabel Reséndiz-Rodríguez, Adriana Martínez-Hernández, Angélica Contreras-Cubas, Cecilia Islas-Andrade, Sergio Zerrweck, Carlos García-Ortiz, Humberto Orozco, Lorena Orphanet J Rare Dis Research BACKGROUND: We investigated pathogenic DYRK1B variants causative of abdominal obesity-metabolic syndrome 3 (AOMS3) in a group of patients originally diagnosed with type 2 diabetes. All DYRK1B exons were analyzed in a sample of 509 unrelated adults with type 2 diabetes and 459 controls, all belonging to the DMS1 SIGMA-cohort (ExAC). We performed in silico analysis on missense variants using Variant Effect Predictor software. To evaluate co-segregation, predicted pathogenic variants were genotyped in other family members. We performed molecular dynamics analysis for the co-segregating variants. RESULTS: After filtering, Mendelian genotypes were confirmed in two probands bearing two novel variants, p.Arg252His and p.Lys68Gln. Both variants co-segregated with the AOMS3 phenotype in classic dominant autosomal inheritance with full penetrance. In silico analysis revealed impairment of the DYRK1B protein function by both variants. For the first time, we describe age-dependent variable expressivity of this entity, with central obesity and insulin resistance apparent in childhood; morbid obesity, severe hypertriglyceridemia, and labile type 2 diabetes appearing before 40 years of age; and hypertension emerging in the fifth decade of life. We also report the two youngest individuals suffering from AOMS3. CONCLUSIONS: Monogenic forms of metabolic diseases could be misdiagnosed and should be suspected in families with several affected members and early-onset metabolic phenotypes that are difficult to control. Early diagnostic strategies and medical interventions, even before symptoms or complications appear, could be useful. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13023-021-01924-z. BioMed Central 2021-06-30 /pmc/articles/PMC8247206/ /pubmed/34193236 http://dx.doi.org/10.1186/s13023-021-01924-z Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Mendoza-Caamal, Elvia C. Barajas-Olmos, Francisco Mirzaeicheshmeh, Elaheh Ilizaliturri-Flores, Ian Aguilar-Salinas, Carlos A. Gómez-Velasco, Donaji V. Cicerón-Arellano, Isabel Reséndiz-Rodríguez, Adriana Martínez-Hernández, Angélica Contreras-Cubas, Cecilia Islas-Andrade, Sergio Zerrweck, Carlos García-Ortiz, Humberto Orozco, Lorena Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title | Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title_full | Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title_fullStr | Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title_full_unstemmed | Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title_short | Two novel variants in DYRK1B causative of AOMS3: expanding the clinical spectrum |
title_sort | two novel variants in dyrk1b causative of aoms3: expanding the clinical spectrum |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247206/ https://www.ncbi.nlm.nih.gov/pubmed/34193236 http://dx.doi.org/10.1186/s13023-021-01924-z |
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