Exome sequencing (ES) of a pediatric cohort with chronic endocrine diseases: a single-center study (within the framework of the TRANSLATE-NAMSE project).

Exome sequencing TRANSLATE-NAMSE chronic pediatric endocrine diseases multidisciplinary case conferences rare diseases

Journal

Endocrine
ISSN: 1559-0100
Titre abrégé: Endocrine
Pays: United States
ID NLM: 9434444

Informations de publication

Date de publication:
08 Nov 2023
Historique:
received: 24 07 2023
accepted: 18 10 2023
medline: 9 11 2023
pubmed: 9 11 2023
entrez: 8 11 2023
Statut: aheadofprint

Résumé

Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases. We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATE‑NAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others. The overall diagnostic yield was 34.9% (n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses. ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling.

Sections du résumé

BACKGROUND BACKGROUND
Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases.
METHODS METHODS
We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATE‑NAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others.
RESULTS RESULTS
The overall diagnostic yield was 34.9% (n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses.
CONCLUSIONS CONCLUSIONS
ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling.

Identifiants

DOI: 10.1007/s12020-023-03581-7 PMID: 37940764
pubmed: 37940764
doi: 10.1007/s12020-023-03581-7
pii: 10.1007/s12020-023-03581-7
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Informations de copyright

© 2023. The Author(s).

Références

Shlomo M., Auchus R.J., Goldfine A.B., Koenig R.J., Rosen C.J. Williams textbook of endocrinology. Philadelphia: Elsevier; 2020.
Bundesausschuss IbG: TRANSLATE-NAMSE – Verbesserung der Versorgung von Menschen mit seltenen Erkrankungen durch Umsetzung von im nationalen Aktionsplan (NAMSE) konsentierten Maßnahmen. https://innovationsfonds.g-ba.de/projekte/neue-versorgungsformen/translate-namse-verbesserung-der-versorgung-von-menschen-mit-seltenen-erkrankungen-durch-umsetzung-von-im-nationalen-aktionsplan-namse-konsentierten-massnahmen.78 (2017). Accessed 20.01.2023.
S. Kohler, M. Gargano, N. Matentzoglu, L.C. Carmody, D. Lewis-Smith, N.A. Vasilevsky et al. The human phenotype ontology in 2021. Nucleic Acids Res 49(D1), D1207–D1217 (2021). https://doi.org/10.1093/nar/gkaa1043
doi: 10.1093/nar/gkaa1043 pubmed: 33264411
E.R. Riggs, E.F. Andersen, A.M. Cherry, S. Kantarci, H. Kearney, A. Patel et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22(2), 245–257 (2020). https://doi.org/10.1038/s41436-019-0686-8
doi: 10.1038/s41436-019-0686-8 pubmed: 31690835
S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5), 405–424 (2015). https://doi.org/10.1038/gim.2015.30
doi: 10.1038/gim.2015.30 pubmed: 25741868 pmcid: 4544753
A.N. Abou Tayoun, T. Pesaran, M.T. DiStefano, A. Oza, H.L. Rehm, L.G. Biesecker et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum. Mutat. 39(11), 1517–1524 (2018). https://doi.org/10.1002/humu.23626
doi: 10.1002/humu.23626 pubmed: 30192042 pmcid: 6185798
Falb R.J., Muller A.J., Klein W., Grimmel M., Grasshoff U., Spranger S., et al. Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex. J Med Genet. 2021. https://doi.org/10.1136/jmedgenet-2021-108064 .
M. Granzow, N. Paramasivam, K. Hinderhofer, C. Fischer, S. Chotewutmontri, L. Kaufmann et al. Loss of function of PGAP1 as a cause of severe encephalopathy identified by Whole Exome Sequencing: Lessons of the bioinformatics pipeline. Mol. Cell Probes 29(5), 323–329 (2015). https://doi.org/10.1016/j.mcp.2015.05.012
doi: 10.1016/j.mcp.2015.05.012 pubmed: 26050939
P. Freeman, R. Hart, L. Gretton, A. Brookes, R. Dalgleish, VariantValidator: Accurate validation, mapping and formatting of sequence variation descriptions. Hum. Mutat. 39, 61–68 (2018)
doi: 10.1002/humu.23348 pubmed: 28967166
Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC Text with EEA relevance. 2014. p. 1-76.
K.J. Karczewski, L.C. Francioli, G. Tiao, B.B. Cummings, J. Alfoldi, Q. Wang et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581(7809), 434–443 (2020). https://doi.org/10.1038/s41586-020-2308-7
doi: 10.1038/s41586-020-2308-7 pubmed: 32461654 pmcid: 7334197
MacDonald J., Ziman R., Yuen R., Feuk L., Scherer S. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2013.
N. Sobreira, F. Schiettecatte, C. Boehm, D. Valle, A. Hamosh, New tools for Mendelian disease gene identification: PhenoDB variant analysis module; and GeneMatcher, a web-based tool for linking investigators with an interest in the same gene. Hum. Mutat. 36(4), 425–431 (2015). https://doi.org/10.1002/humu.22769
doi: 10.1002/humu.22769 pubmed: 25684268 pmcid: 4820250
N. Sobreira, F. Schiettecatte, D. Valle, A. Hamosh, GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36(10), 928–930 (2015). https://doi.org/10.1002/humu.22844
doi: 10.1002/humu.22844 pubmed: 26220891 pmcid: 4833888
J.J. Hughes, E. Alkhunaizi, P. Kruszka, L.C. Pyle, D.K. Grange, S.I. Berger et al. Loss-of-Function Variants in PPP1R12A: From Isolated Sex Reversal to Holoprosencephaly Spectrum and Urogenital Malformations. Am. J. Hum. Genet 106(1), 121–128 (2020). https://doi.org/10.1016/j.ajhg.2019.12.004
doi: 10.1016/j.ajhg.2019.12.004 pubmed: 31883643
Li D., Wang Q., Gong N.N., Kurolap A., Feldman H.B., Boy N., et al. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Sci Adv. 2021;7(20). https://doi.org/10.1126/sciadv.abf2066 .
F. Tessadori, K. Duran, K. Knapp, M. Fellner; Deciphering Developmental Disorders S, S. Smithson et al. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome. Am. J. Hum. Genet 109(4), 750–758 (2022). https://doi.org/10.1016/j.ajhg.2022.02.003
doi: 10.1016/j.ajhg.2022.02.003 pubmed: 35202563 pmcid: 9069069
F. Tessadori, K. Duran, K. Knapp, M. Fellner, S. Smithson, A. Beleza Meireles et al. Recurrent de novo missense variants across multiple histone H4 genes underlie a neurodevelopmental syndrome. Am. J. Hum. Genet. 109(4), 750–758 (2022). https://doi.org/10.1016/j.ajhg.2022.02.003
doi: 10.1016/j.ajhg.2022.02.003 pubmed: 35202563 pmcid: 9069069
A. Vanderver, L. Adang, F. Gavazzi, K. McDonald, G. Helman, D.B. Frank et al. Janus Kinase Inhibition in the Aicardi-Goutieres Syndrome. N. Engl. J. Med 383(10), 986–989 (2020). https://doi.org/10.1056/NEJMc2001362
doi: 10.1056/NEJMc2001362 pubmed: 32877590 pmcid: 7495410
A.P. Abreu, A. Dauber, D.B. Macedo, S.D. Noel, V.N. Brito, J.C. Gill et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med 368(26), 2467–2475 (2013). https://doi.org/10.1056/NEJMoa1302160
doi: 10.1056/NEJMoa1302160 pubmed: 23738509
Ji J., Shen L., Bootwalla M., Quindipan C., Tatarinova T., Maglinte D.T., et al. A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. 2019;5(2). https://doi.org/10.1101/mcs.a003756 .
K. Retterer, J. Juusola, M.T. Cho, P. Vitazka, F. Millan, F. Gibellini et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 18(7), 696–704 (2016). https://doi.org/10.1038/gim.2015.148
doi: 10.1038/gim.2015.148 pubmed: 26633542
S. Srivastava, J.A. Love-Nichols, K.A. Dies, D.H. Ledbetter, C.L. Martin, W.K. Chung et al. Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genet Med 21(11), 2413–2421 (2019). https://doi.org/10.1038/s41436-019-0554-6
doi: 10.1038/s41436-019-0554-6 pubmed: 31182824
T.Y. Tan, O.J. Dillon, Z. Stark, D. Schofield, K. Alam, R. Shrestha et al. Diagnostic Impact and Cost-effectiveness of Whole-Exome Sequencing for Ambulant Children With Suspected Monogenic Conditions. JAMA Pediatr. 171(9), 855–862 (2017). https://doi.org/10.1001/jamapediatrics.2017.1755
doi: 10.1001/jamapediatrics.2017.1755 pubmed: 28759686
M.H.Y. Tsang, A.T.G. Chiu, B.M.H. Kwong, R. Liang, M.H.C. Yu, K.S. Yeung et al. Diagnostic value of whole-exome sequencing in Chinese pediatric-onset neuromuscular patients. Mol. Genet Genom. Med 8(5), e1205 (2020). https://doi.org/10.1002/mgg3.1205
doi: 10.1002/mgg3.1205
T. Brunet, R. Jech, M. Brugger, R. Kovacs, B. Alhaddad, G. Leszinski et al. De novo variants in neurodevelopmental disorders-experiences from a tertiary care center. Clin. Genet 100(1), 14–28 (2021). https://doi.org/10.1111/cge.13946
doi: 10.1111/cge.13946 pubmed: 33619735
H.S. Smith, J.M. Swint, S.R. Lalani, J.M. Yamal, M.C. de Oliveira Otto, S. Castellanos et al. Clinical application of genome and exome sequencing as a diagnostic tool for pediatric patients: a scoping review of the literature. Genet Med 21(1), 3–16 (2019). https://doi.org/10.1038/s41436-018-0024-6
doi: 10.1038/s41436-018-0024-6 pubmed: 29760485
P.J. Newey, Clinical genetic testing in endocrinology: Current concepts and contemporary challenges. Clin. Endocrinol. (Oxf.) 91(5), 587–607 (2019). https://doi.org/10.1111/cen.14053
doi: 10.1111/cen.14053
H.C. Martin, W.D. Jones, R. McIntyre, G. Sanchez-Andrade, M. Sanderson, J.D. Stephenson et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science 362(6419), 1161–1164 (2018). https://doi.org/10.1126/science.aar6731
doi: 10.1126/science.aar6731 pubmed: 30409806 pmcid: 6726470

Auteurs

Sebastian Gippert (S)

Division of Pediatric Endocrinology and Diabetes, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany and Center for Rare Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Matias Wagner (M)

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Institute for Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany.
ORCID: 0000-0002-4454-8823

Theresa Brunet (T)

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Department of Pediatric Neurology and Developmental Medicine, Hauner Children's Hospital, Ludwig Maximilian University of Munich, Munich, Germany.

Riccardo Berruti (R)

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.

Melanie Brugger (M)

Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
ORCID: 0000-0002-6920-8550

Eva M C Schwaibold (EMC)

Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
ORCID: 0000-0003-2708-9642

Tobias B Haack (TB)

Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany and Centre for Rare Diseases, University of Tuebingen, Tübingen, Germany.
ORCID: 0000-0001-6033-4836

Georg F Hoffmann (GF)

Division of Pediatric Endocrinology and Diabetes, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany and Center for Rare Diseases, University Hospital Heidelberg, Heidelberg, Germany.
ORCID: 0000-0002-6593-896X

Markus Bettendorf (M)

Division of Pediatric Endocrinology and Diabetes, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany and Center for Rare Diseases, University Hospital Heidelberg, Heidelberg, Germany.
ORCID: 0000-0002-7988-0316

Daniela Choukair (D)

Division of Pediatric Endocrinology and Diabetes, Center for Pediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany and Center for Rare Diseases, University Hospital Heidelberg, Heidelberg, Germany. daniela.choukair@med.uni-heidelberg.de.
ORCID: 0000-0002-1631-3883

Classifications MeSH