{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T16:29:45Z","timestamp":1770827385264,"version":"3.50.1"},"reference-count":40,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","award":["UIDB\/00215\/2020, UIDP\/00215\/2020 and LA\/P\/0064\/2020"],"award-info":[{"award-number":["UIDB\/00215\/2020, UIDP\/00215\/2020 and LA\/P\/0064\/2020"]}]},{"name":"DEFI - CHUPorto","award":["2017 DEFI-CHUP, E.P.E. and 2015 (145\/12)"],"award-info":[{"award-number":["2017 DEFI-CHUP, E.P.E. and 2015 (145\/12)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>We describe an infant female with a syndromic neurodevelopmental clinical phenotype and increased chromosome instability as cellular phenotype. Genotype characterization revealed heterozygous variants in genes directly or indirectly linked to DNA repair: a de novo X-linked HDAC8 pathogenic variant, a paternally inherited FANCG pathogenic variant and a maternally inherited BRCA2 variant of uncertain significance. The full spectrum of the phenotype cannot be explained by any of the heterozygous variants on their own; thus, a synergic contribution is proposed. Complementation studies showed that the FANCG gene from the Fanconi Anaemia\/BRCA (FA\/BRCA) DNA repair pathway was impaired, indicating that the variant in FANCG contributes to the cellular phenotype. The patient\u2019s chromosome instability represents the first report where heterozygous variant(s) in the FA\/BRCA pathway are implicated in the cellular phenotype. We propose that a multigenic contribution of heterozygous variants in HDAC8 and the FA\/BRCA pathway might have a role in the phenotype of this neurodevelopmental disorder. The importance of these findings may have repercussion in the clinical management of other cases with a similar synergic contribution of heterozygous variants, allowing the establishment of new genotype\u2013phenotype correlations and motivating the biochemical study of the underlying mechanisms.<\/jats:p>","DOI":"10.3390\/genes13010078","type":"journal-article","created":{"date-parts":[[2021,12,29]],"date-time":"2021-12-29T02:31:27Z","timestamp":1640745087000},"page":"78","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Can the Synergic Contribution of Multigenic Variants Explain the Clinical and Cellular Phenotypes of a Neurodevelopmental Disorder?"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3274-2474","authenticated-orcid":false,"given":"Nuno","family":"Maia","sequence":"first","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Jo\u00e3o","family":"Nabais S\u00e1","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0556-406X","authenticated-orcid":false,"given":"Cl\u00e1udia","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Citogen\u00e9tica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fl\u00e1via","family":"Santos","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C\u00e9lia Azevedo","family":"Soares","sequence":"additional","affiliation":[{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"},{"name":"Servi\u00e7o de Gen\u00e9tica M\u00e9dica, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catarina","family":"Prior","sequence":"additional","affiliation":[{"name":"Unidade de Neurodesenvolvimento do Servi\u00e7o de Pediatria do Centro Materno-Infantil do Norte (CMIN), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4050-651 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nataliya","family":"Tkachenko","sequence":"additional","affiliation":[{"name":"Servi\u00e7o de Gen\u00e9tica M\u00e9dica, Centro de Gen\u00e9tica M\u00e9dica Doutor Jacinto Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8594-6377","authenticated-orcid":false,"given":"Ros\u00e1rio","family":"Santos","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2131-0484","authenticated-orcid":false,"given":"Arjan P. M.","family":"de Brouwer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 GA Nijmegen, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2980-7399","authenticated-orcid":false,"given":"Ariana","family":"Jacome","sequence":"additional","affiliation":[{"name":"Chromosome Instability and Dynamics Lab. (CID), Instituto de Inova\u00e7\u00e3o e Investiga\u00e7\u00e3o (i3S), Universidade do Porto, 4200-135 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4281-5438","authenticated-orcid":false,"given":"Beatriz","family":"Porto","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio Citogen\u00e9tica, Instituto de Ci\u00eancias Biom\u00e9dicas Abel Salazar (ICBAS), Universidade do Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6507-222X","authenticated-orcid":false,"given":"Paula","family":"Jorge","sequence":"additional","affiliation":[{"name":"Unidade de Gen\u00e9tica Molecular, Centro de Gen\u00e9tica M\u00e9dica Jacinto de Magalh\u00e3es (CGM), Centro Hospitalar Universit\u00e1rio do Porto (CHUPorto), 4099-028 Porto, Portugal"},{"name":"Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory for Integrative and Translational Research in Population Health (ITR), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, 4050-313 Porto, Portugal"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1186\/s13073-017-0498-x","article-title":"Recurrent de novo mutations in neurodevelopmental disorders: Properties and clinical implications","volume":"9","author":"Wilfert","year":"2017","journal-title":"Genome Med."},{"key":"ref_2","unstructured":"Association, A.P. (2013). Diagnostic and Statistical Manual of Mental Disorders, The American Psychiatric Association. [5th ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.tins.2020.05.004","article-title":"Neurodevelopmental Disorders: From Genetics to Functional Pathways","volume":"43","author":"Parenti","year":"2020","journal-title":"Trends Neurosci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nrg3999","article-title":"Genetic studies in intellectual disability and related disorders","volume":"17","author":"Vissers","year":"2016","journal-title":"Nat. Rev. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4223","DOI":"10.1182\/blood-2005-10-4240","article-title":"Molecular pathogenesis of Fanconi anemia: Recent progress","volume":"107","author":"Taniguchi","year":"2006","journal-title":"Blood"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.beha.2014.10.002","article-title":"Fanconi anemia and the development of leukemia","volume":"27","author":"Alter","year":"2014","journal-title":"Best Pr. Res. Clin. Haematol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Auerbach, A.D. (2003). Diagnosis of fanconi anemia by diepoxybutane analysis. Curr. Protoc. Hum. Genet., 37.","DOI":"10.1002\/0471142905.hg0807s37"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1038\/nature11863","article-title":"Fanconi anaemia and the repair of Watson and Crick DNA crosslinks","volume":"493","author":"Kottemann","year":"2013","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8829","DOI":"10.1038\/ncomms9829","article-title":"A novel Fanconi anaemia subtype associated with a dominant-negative mutation in RAD51","volume":"6","author":"Ameziane","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e140","DOI":"10.1093\/nar\/gkx557","article-title":"Understanding mutational effects in digenic diseases","volume":"45","author":"Gazzo","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11878","DOI":"10.1073\/pnas.1815601116","article-title":"Predicting disease-causing variant combinations","volume":"116","author":"Papadimitriou","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D900","DOI":"10.1093\/nar\/gkv1068","article-title":"DIDA: A curated and annotated digenic diseases database","volume":"44","author":"Gazzo","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1093\/nar\/16.3.1215","article-title":"A simple salting out procedure for extracting DNA from human nucleated cells","volume":"16","author":"Miller","year":"1988","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7155","DOI":"10.1093\/nar\/15.17.7155","article-title":"RNA splice junctions of different classes of eukaryotes: Sequence statistics and functional implications in gene expression","volume":"15","author":"Shapiro","year":"1987","journal-title":"Nucleic Acids Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1089\/1066527041410418","article-title":"Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals","volume":"11","author":"Yeo","year":"2004","journal-title":"J. Comput. Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1089\/cmb.1997.4.311","article-title":"Improved splice site detection in Genie","volume":"4","author":"Reese","year":"1997","journal-title":"J. Comput. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1093\/nar\/29.5.1185","article-title":"GeneSplicer: A new computational method for splice site prediction","volume":"29","author":"Pertea","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1007\/s004390100505","article-title":"Nomenclature for the description of human sequence variations","volume":"109","author":"Antonarakis","year":"2001","journal-title":"Hum. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/(SICI)1098-1004(200001)15:1<7::AID-HUMU4>3.0.CO;2-N","article-title":"Mutation nomenclature extensions and suggestions to describe complex mutations: A discussion","volume":"15","author":"Antonarakis","year":"2000","journal-title":"Hum. Mutat."},{"key":"ref_21","first-page":"405","article-title":"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","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med. Off. J. Am. Coll. Med Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: Improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1101\/gr.138115.112","article-title":"Copy number variation detection and genotyping from exome sequence data","volume":"22","author":"Krumm","year":"2012","journal-title":"Genome Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"524","DOI":"10.1016\/j.ajhg.2009.03.010","article-title":"DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources","volume":"84","author":"Firth","year":"2009","journal-title":"Am. J. Hum. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1182\/blood.V73.2.391.391","article-title":"International Fanconi Anemia Registry: Relation of clinical symptoms to diepoxybutane sensitivity","volume":"73","author":"Auerbach","year":"1989","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1136\/jmg.2006.044719","article-title":"A comprehensive strategy for the subtyping of patients with Fanconi anaemia: Conclusions from the Spanish Fanconi Anemia Research Network","volume":"44","author":"Jacome","year":"2007","journal-title":"J. Med. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1016\/S0301-472X(02)00782-8","article-title":"Phenotypic correction of primary Fanconi anemia T cells with retroviral vectors as a diagnostic tool","volume":"30","author":"Hanenberg","year":"2002","journal-title":"Exp. Hematol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"S133","DOI":"10.1007\/s10545-010-9048-z","article-title":"Four years of expanded newborn screening in Portugal with tandem mass spectrometry","volume":"33","author":"Vilarinho","year":"2010","journal-title":"J. Inherit. Metab. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1136\/jmedgenet-2012-100921","article-title":"X-exome sequencing identifies a HDAC8 variant in a large pedigree with X-linked intellectual disability, truncal obesity, gynaecomastia, hypogonadism and unusual face","volume":"49","author":"Harakalova","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2888","DOI":"10.1093\/hmg\/ddu002","article-title":"Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance","volume":"23","author":"Kaiser","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/jhg.2014.60","article-title":"Exome sequencing identifies a de novo mutation in HDAC8 associated with Cornelia de Lange syndrome","volume":"59","author":"Feng","year":"2014","journal-title":"J. Hum. Genet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"804","DOI":"10.1002\/humu.23012","article-title":"Identification of Intellectual Disability Genes in Female Patients with A Skewed X Inactivation Pattern","volume":"37","author":"Fieremans","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"564","DOI":"10.1111\/cge.12717","article-title":"Expanding the clinical spectrum of the \u2018HDAC8-phenotype\u2019\u2014Implications for molecular diagnostics, counseling and risk prediction","volume":"89","author":"Parenti","year":"2016","journal-title":"Clin. Genet."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1159\/000491613","article-title":"A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome","volume":"47","author":"Gao","year":"2018","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"15064","DOI":"10.1073\/pnas.0404603101","article-title":"Crystal structure of a eukaryotic zinc-dependent histone deacetylase, human HDAC8, complexed with a hydroxamic acid inhibitor","volume":"101","author":"Vannini","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","first-page":"1156","article-title":"X-linked diseases: Susceptible females","volume":"22","author":"Migeon","year":"2020","journal-title":"Genet. Med. Off. J. Am. Coll. Med. Genet."},{"key":"ref_38","first-page":"4000","article-title":"Susceptibility of Fanconi\u2019s anemia lymphoblasts to DNA-cross-linking and alkylating agents","volume":"42","author":"Ishida","year":"1982","journal-title":"Cancer Res."},{"key":"ref_39","unstructured":"Frohnmayer, L.V.R.S., and Wirkkula, L. (2020). Fanconi Anemia Clinical Care Guidelines, Fanconi Anemia Research Fund. [5th ed.]."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Belo, H., Silva, G., Cardoso, B.A., Porto, B., Minguillon, J., Barbot, J., Coutinho, J., Casado, J.A., Benedito, M., and Saturnino, H. (2015). Epigenetic Alterations in Fanconi Anaemia: Role in Pathophysiology and Therapeutic Potential. 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