Constraint and conservation of paired-type homeodomains predicts the clinical outcome of missense variants of uncertain significance.
Adolescent
Amino Acid Sequence
Autism Spectrum Disorder
/ genetics
Child, Preschool
Conserved Sequence
DNA Mutational Analysis
Epilepsy
/ genetics
Female
Homeodomain Proteins
/ genetics
Humans
Infant
Infant, Newborn
Intellectual Disability
/ genetics
Male
Mutation, Missense
Pedigree
Phenotype
Protein Domains
Transcription Factors
/ genetics
Young Adult
aristaless-related homeobox
autism spectrum disorder
intellectual disability
seizure
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
08 2020
08 2020
Historique:
received:
30
10
2019
revised:
26
02
2020
accepted:
03
05
2020
pubmed:
10
5
2020
medline:
9
11
2021
entrez:
9
5
2020
Statut:
ppublish
Résumé
The need to interpret the pathogenicity of novel missense variants of unknown significance identified in the homeodomain of X-chromosome aristaless-related homeobox (ARX) gene prompted us to assess the utility of conservation and constraint across these domains in multiple genes compared to conventional in vitro functional analysis. Pathogenic missense variants clustered in the homeodomain of ARX contribute to intellectual disability (ID) and epilepsy, with and without brain malformation in affected males. Here we report novel c.1112G>A, p.Arg371Gln and c.1150C>T, p.Arg384Cys variants in male patients with ID and severe seizures. The third case of a male patient with a c.1109C>T, p.Ala370Val variant is perhaps the first example of ID and autism spectrum disorder (ASD), without seizures or brain malformation. We compiled data sets of pathogenic variants from ClinVar and presumed benign variation from gnomAD and demonstrated that the high levels of sequence conservation and constraint of benign variation within the homeodomain impacts upon the ability of publicly available in silico prediction tools to accurately discern likely benign from likely pathogenic variants in these data sets. Despite this, considering the inheritance patterns of the genes and disease variants with the conservation and constraint of disease variants affecting the homeodomain in conjunction with current clinical assessments may assist in predicting the pathogenicity of missense variants, particularly for genes with autosomal recessive and X-linked patterns of disease inheritance, such as ARX. In vitro functional analysis demonstrates that the transcriptional activity of all three variants was diminished compared to ARX-Wt. We review the associated phenotypes of the published cases of patients with ARX homeodomain variants and propose expansion of the ARX-related phenotype to include severe ID and ASD without brain malformations or seizures. We propose that the use of the constraint and conservation data in conjunction with consideration of the patient phenotype and inheritance pattern may negate the need for the experimental functional validation currently required to achieve a diagnosis.
Substances chimiques
ARX protein, human
0
Homeodomain Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1407-1424Informations de copyright
© 2020 Wiley Periodicals LLC.
Références
Carter, H., Douville, C., Stenson, P. D., Cooper, D. N., & Karchin, R. (2013). Identifying Mendelian disease genes with the variant effect scoring tool. Bmc Genomics, 14(Suppl 3), S3. https://doi.org/10.1186/1471-2164-14-S3-S3
Chang, X., & Wang, K. (2012). wANNOVAR: Annotating genetic variants for personal genomes via the web. Journal of Medical Genetics, 49(7), 433-436. https://doi.org/10.1136/jmedgenet-2012-100918
Chi, Y. I. (2005). Homeodomain revisited: A lesson from disease-causing mutations. Human Genetics, 116(6), 433-444. https://doi.org/10.1007/s00439-004-1252-1
Choi, Y., & Chan, A. P. (2015). PROVEAN web server: A tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics, 31(16), 2745-2747. https://doi.org/10.1093/bioinformatics/btv195
Collombat, P., Hecksher-Sorensen, J., Broccoli, V., Krull, J., Ponte, I., Mundiger, T., … Mansouri, A. (2005). The simultaneous loss of Arx and Pax4 genes promotes a somatostatin-producing cell fate specification at the expense of the alpha- and beta-cell lineages in the mouse endocrine pancreas. Development, 132(13), 2969-2980. https://doi.org/10.1242/dev.01870
Collombat, P., Mansouri, A., Hecksher-Sorensen, J., Serup, P., Krull, J., Gradwohl, G., & Gruss, P. (2003). Opposing actions of Arx and Pax4 in endocrine pancreas development. Genes and Development, 17(20), 2591-2603. https://doi.org/10.1101/gad.269003
Conti, V., Marini, C., Gana, S., Sudi, J., Dobyns, W. B., & Guerrini, R. (2011). Corpus callosum agenesis, severe mental retardation, epilepsy, and dyskinetic quadriparesis due to a novel mutation in the homeodomain of ARX. American Journal of Medical Genetics. Part A, 155A(4), 892-897. https://doi.org/10.1002/ajmg.a.33923
D'Elia, A. V., Tell, G., Paron, I., Pellizzari, L., Lonigro, R., & Damante, G. (2001). Missense mutations of human homeoboxes: A review. Human Mutation, 18(5), 361-374. https://doi.org/10.1002/humu.1207
DePristo, M. A., Banks, E., Poplin, R., Garimella, K. V., Maguire, J. R., Hartl, C., … Daly, M. J. (2011). A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genetics, 43(5), 491-498. https://doi.org/10.1038/ng.806
Dobyns, W. B., Berry-Kravis, E., Havernick, N. J., Holden, K. R., & Viskochil, D. (1999). X-linked lissencephaly with absent corpus callosum and ambiguous genitalia. American Journal of Medical Genetics, 86(4), 331-337. https://doi.org/10.1002/(SICI)1096-8628(19991008)86:4<331::AID-AJMG7>3.0.CO;2-P
Douville, C., Masica, D. L., Stenson, P. D., Cooper, D. N., Gygax, D. M., Kim, R., … Karchin, R. (2016). Assessing the pathogenicity of insertion and deletion variants with the variant effect scoring tool (VEST-Indel). Human Mutation, 37(1), 28-35. https://doi.org/10.1002/humu.22911
Epi, K. C., Epilepsy Phenome/Genome, P., Allen, A. S., Berkovic, S. F., Cossette, P., Delanty, N., … Winawer, M. R. (2013). De novo mutations in epileptic encephalopathies. Nature, 501(7466), 217-221. https://doi.org/10.1038/nature12439
Fullston, T., Finnis, M., Hackett, A., Hodgson, B., Brueton, L., Baynam, G., … Gecz, J. (2011). Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene. Clinical Genetics, 80(6), 510-522. https://doi.org/10.1111/j.1399-0004.2011.01685.x
Fulp, C. T., Cho, G., Marsh, E. D., Nasrallah, I. M., Labosky, P. A., & Golden, J. A. (2008). Identification of Arx transcriptional targets in the developing basal forebrain. Human Molecular Genetics, 17(23), 3740-3760.
Gecz, J., Cloosterman, D., & Partington, M. (2006). ARX: A gene for all seasons. Current Opinion in Genetics and Development, 16(3), 308-316. https://doi.org/10.1016/j.gde.2006.04.003
Haer-Wigman, L., van Zelst-Stams, W. A., Pfundt, R., van den Born, L. I., Klaver, C. C., Verheij, J. B., … Yntema, H. G. (2017). Diagnostic exome sequencing in 266 Dutch patients with visual impairment. European Journal of Human Genetics, 25(5), 591-599. https://doi.org/10.1038/ejhg.2017.9
Havrilla, J. M., Pedersen, B. S., Layer, R. M., & Quinlan, A. R. (2019). A map of constrained coding regions in the human genome. Nature Genetics, 51(1), 88-95. https://doi.org/10.1038/s41588-018-0294-6
Helbig, K. L., Farwell Hagman, K. D., Shinde, D. N., Mroske, C., Powis, Z., Li, S., … Helbig, I. (2016). Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genetics in Medicine, 18(9), 898-905. https://doi.org/10.1038/gim.2015.186
Kato, M., Das, S., Petras, K., Kitamura, K., Morohashi, K., Abuelo, D. N., … Dobyns, W. B. (2004). Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Human Mutation, 23(2), 147-159. https://doi.org/10.1002/humu.10310
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alfoldi, J., Wang, Q., … MacArthur, D. G. (2019). Variation across 141,456 human exome and genomes reveals the spectrum of loss-of-function intolerance across human protien coding genes. bioRxiv, 1-39. https://doi.org/10.1101/531210
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014). A general framework for estimating the relative pathogenicity of human genetic variants. Nature Genetics, 46(3), 310-315. https://doi.org/10.1038/ng.2892
Kitamura, K., Itou, Y., Yanazawa, M., Ohsawa, M., Suzuki-Migishima, R., Umeki, Y., … Goto, Y. (2009). Three human ARX mutations cause the lissencephaly-like and mental retardation with epilepsy-like pleiotropic phenotypes in mice. Human Molecular Genetics, 18(19), 3708-3724. https://doi.org/10.1093/hmg/ddp318
Kitamura, K., Yanazawa, M., Sugiyama, N., Miura, H., Iizuka-Kogo, A., Kusaka, M., … Morohashi, K. (2002). Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genetics, 32(3), 359-369. https://doi.org/10.1038/ng1009
Landrum, M. J., Lee, J. M., Riley, G. R., Jang, W., Rubinstein, W. S., Church, D. M., & Maglott, D. R. (2014). ClinVar: Public archive of relationships among sequence variation and human phenotype. Nucleic Acids Research, 42(Database issue), D980-985. https://doi.org/10.1093/nar/gkt1113
Li, H., & Durbin, R. (2009). Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics, 25(14), 1754-1760. https://doi.org/10.1093/bioinformatics/btp324
Marsh, E., Fulp, C., Gomez, E., Nasrallah, I., Minarcik, J., Sudi, J., … Golden, J. A. (2009). Targeted loss of Arx results in a developmental epilepsy mouse model and recapitulates the human phenotype in heterozygous females. Brain, 132(Pt 6), 1563-1576. https://doi.org/10.1093/brain/awp107
Mattiske, T., Tan, M. H., Dearsley, O., Cloosterman, D., Hii, C. S., Gecz, J., & Shoubridge, C. (2018). Regulating transcriptional activity by phosphorylation: A new mechanism for the ARX homeodomain transcription factor. PLOS One, 13(11):e0206914. https://doi.org/10.1371/journal.pone.0206914
McKenzie, O., Ponte, I., Mangelsdorf, M., Finnis, M., Colasante, G., Shoubridge, C., … Broccoli, V. (2007). Aristaless-related homeobox gene, the gene responsible for west syndrome and related disorders, is a groucho/transducin-like enhancer of split dependent transcriptional repressor. Neuroscience, 146(1), 236-247. https://doi.org/10.1016/j.neuroscience.2007.01.038
Mirzaa, G. M., Enyedi, L., Parsons, G., Collins, S., Medne, L., Adams, C., … Christian, S. (2014). Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: Five novel mutations and review of the literature. American journal of medical genetics. Part A, 164, 2879-2886. https://doi.org/10.1002/ajmg.a.36707
Mirzaa, G. M., Paciorkowski, A. R., Marsh, E. D., Berry-Kravis, E. M., Medne, L., Alkhateeb, A., … Das, S. (2013). CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatric Neurology, 48(5), 367-377. https://doi.org/10.1016/j.pediatrneurol.2012.12.030
Noyes, M. B., Christensen, R. G., Wakabayashi, A., Stormo, G. D., Brodsky, M. H., & Wolfe, S. A. (2008). Analysis of homeodomain specificities allows the family-wide prediction of preferred recognition sites. Cell, 133(7), 1277-1289. https://doi.org/10.1016/j.cell.2008.05.023
Ploski, J. E., Shamsher, M. K., & Radu, A. (2004). Paired-type homeodomain transcription factors are imported into the nucleus by karyopherin 13. Molecular and Cellular Biology, 24(11), 4824-4834. https://doi.org/10.1128/MCB.24.11.4824-4834.2004
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J., & Kircher, M. (2019). CADD: Predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Research, 47(D1), D886-D894. https://doi.org/10.1093/nar/gky1016
Reva, B., Antipin, Y., & Sander, C. (2011). Predicting the functional impact of protein mutations: Application to cancer genomics. Nucleic Acids Research, 39(17), e118. https://doi.org/10.1093/nar/gkr407
Scheffer, I. E., Wallace, R. H., Phillips, F. L., Hewson, P., Reardon, K., Parasivam, G., … Mulley, J. C. (2002). X-linked myoclonic epilepsy with spasticity and intellectual disability: Mutation in the homeobox gene ARX. Neurology, 59(3), 348-356.
Shoubridge, C., Cloosterman, D., Parkinson-Lawerence, E., Brooks, D., & Gecz, J. (2007). Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. Genomics, 90(1), 59-71. https://doi.org/10.1016/j.ygeno.2007.03.005
Shoubridge, C., Fullston, T., & Gecz, J. (2010). ARX spectrum disorders: Making inroads into the molecular pathology. Human Mutation, 31(8), 889-900. https://doi.org/10.1002/humu.21288
Shoubridge, C., Tan, M. H., Fullston, T., Cloosterman, D., Coman, D., McGillivray, G., … Gecz, J. (2010). Mutations in the nuclear localization sequence of the Aristaless related homeobox; sequestration of mutant ARX with IPO13 disrupts normal subcellular distribution of the transcription factor and retards cell division. PathoGenetics, 3, 1. https://doi.org/10.1186/1755-8417-3-1
Shoubridge, C., Tan, M. H., Seiboth, G., & Gecz, J. (2012). ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Human Molecular Genetics, 21(7), 1639-1647. https://doi.org/10.1093/hmg/ddr601
Stromme, P., Mangelsdorf, M. E., Scheffer, I. E., & Gecz, J. (2002). Infantile spasms, dystonia, and other X-linked phenotypes caused by mutations in Aristaless related homeobox gene, ARX. Brain and Development, 24(5), 266-268.
Stromme, P., Mangelsdorf, M. E., Shaw, M. A., Lower, K. M., Lewis, S. M., Bruyere, H., … Gecz, J. (2002). Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nature Genetics, 30(4), 441-445. https://doi.org/10.1038/ng862
Thevenon, J., Duffourd, Y., Masurel-Paulet, A., Lefebvre, M., Feillet, F., El Chehadeh-Djebbar, S., … Riviere, J. B. (2016). Diagnostic odyssey in severe neurodevelopmental disorders: Toward clinical whole-exome sequencing as a first-line diagnostic test. Clinical Genetics, 89(6), 700-707. https://doi.org/10.1111/cge.12732
Uyanik, G., Aigner, L., Martin, P., Gross, C., Neumann, D., Marschner-Schafer, H., … Winkler, J. (2003). ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology, 61(2), 232-235.
Wang, K., Li, M. Y., & Hakonarson, H. (2010). ANNOVAR: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Research, 38(16), e164. https://doi.org/10.1093/nar/gkq603
Weber, Y. G., Biskup, S., Helbig, K. L., Von Spiczak, S., & Lerche, H. (2017). The role of genetic testing in epilepsy diagnosis and management. Expert Review of Molecular Diagnostics, 17(8), 739-750. https://doi.org/10.1080/14737159.2017.1335598
Willemsen, M. H., & Kleefstra, T. (2014). Making headway with genetic diagnostics of intellectual disabilities. Clinical Genetics, 85(2), 101-110. https://doi.org/10.1111/cge.12244
Wilson, D. S., Sheng, G., Jun, S., & Desplan, C. (1996). Conservation and diversification in homeodomain-DNA interactions: A comparative genetic analysis. Proceedings of the National Academy of Sciences of the United States of America, 93(14), 6886-6891.