Diagnostic exome sequencing in persons with severe intellectual disability
Open accessAbstract
BACKGROUND: The causes of intellectual disability remain largely unknown because of extensive clinical and genetic heterogeneity. METHODS: We evaluated patients with intellectual disability to exclude known causes of the disorder. We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation. RESULTS: We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series. Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. CONCLUSIONS: De novo mutations represent an important cause of intellectual disability; exome sequencing was used as an effective diagnostic strategy for their detection. (Funded by the European Union and others.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The prevalence of ASD in several ID/DD-ascertained cohorts is not quantified, and the prevalence of ID in ASD-ascertained cohorts is known only for a minority subset of participants.
“Because of this bias, the phenotypic overlap between the groups is unclear; the prevalence of ASD in several of the ID/DD-ascertained cohorts is not quantified,13, 14, 15,18,19 and the prevalence of ID in the ASD-ascertained cohorts is known only for a minority subset of participants.11,12”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [14]
The ID/DD cohorts evaluated in the Satterstrom and Coe studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.
“In fact, the ID/DD cohorts evaluated in these two studies overlapped almost completely; each study used samples from five previously published studies, and four of the five were the same studies, accounting for 99% of the samples.11, 12, 13, 14, 15, 16”
From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [14]
CTNNB1 mutations appear among suggestive de novo ASD risk mutations, and about 40% of 126 mutations map to a β-catenin/chromatin remodeling network.
“Mutation of the gene encoding β-catenin, CTNNB1, has been found among suggestive de novo ASD risk contributing mutations (de Ligt et al., 2012; O'Roak et al., 2012b); furthermore, ∼40% of those 126 mutations map to a highly interconnected β-catenin/chromatin remodeling network (O'Roak et al., 2012b).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as de Ligt et al., 2012
CHD2, SYNGAP1, and SYNCRIP are also affected by LoF de novo SNVs in ID, and SYNGAP1 and DPYD are altered in schizophrenia.
“Three other genes affected by de novo CNVs (also picked by NETBAG)—CHD2, SYNGAP1, and SYNCRIP—are also affected by LoF de novo SNVs in ID,50,52 and two (SYNGAP1 and DPYD [MIM 612779]) are altered in schizophrenia.53”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [52]
Genetic approaches have identified causes for more than 1,000 Mendelian and fewer non-Mendelian forms of neurodevelopmental disorders, including intellectual disability, ASD, epilepsy, and schizophrenia.
“Various genetic approaches have been successful in identifying the causes of more than 1,000 Mendelian, and fewer non-Mendelian, forms of neurodevelopmental disorders: prototypical examples are intellectual disability62–68, autism spectrum disorder (ASD)69–77, epilepsy78,79 and schizophrenia80–82.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [66]
Only three genes, CHD8, SCN2A, and SYNGAP1, had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.
“In summary, only three genes [CHD8, SCN2A, and synaptic Ras GTPase activating protein 1 (SYNGAP1)] had two independent truncating de novo mutations in any single study, and no gene had more than three mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
SCN2A mutations have highly variable phenotypic outcomes, as only one of five cases had a history of seizures.
“Lastly, only one of the five cases had a history of seizures [28], suggesting that mutations in SCN2A have highly variable phenotypic outcomes.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands compared with unaffected siblings and has identified novel candidate genes.
“Exome sequencing of ASD/ID families has revealed a significant excess of de novo mutations in probands when compared to unaffected siblings and has identified novel candidate genes contributing to the neurological deficits.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
The strongest effects are observed for de novo loss-of-function or truncating mutations.
“We note that the strongest effects are observed for de novo loss-of-function (or truncating) mutations”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
Many strong neurobiological candidates have emerged from genes disrupted by de novo mutations, including previously identified ASD/ID genes.
“Many strong neurobiological candidates have emerged from the genes disrupted by de novo mutations in these studies, including mutations in previously identified ASD/ID genes.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
Sporadic cases of autism spectrum disorder and intellectual disability are enriched for disruptive de novo mutations.
“New exome sequencing technology has identified novel rare variants and has found that sporadic cases of ASD/ID are enriched for disruptive de novo mutations.”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
ASD cases with truncating CHD8 mutations have significant macrocephaly, whereas all three cases with truncating beta-catenin mutations have microcephaly.
“Strikingly, ASD cases with truncating mutations in CHD8 have significant macrocephaly [44], whereas all three cases with truncating mutations in beta-catenin have microcephaly ([28]; B.J. O’Roak, unpublished).”
From A de novo convergence of autism genetics and molecular neuroscience (2014) · cites this paper as [28]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Miller, D. T., Adam, M. P., Aradhya, S., Biesecker, L. G., Brothman, A. R., Carter, N. P., Church, D. M., Crolla, J. A., Eichler, E. E., Epstein, C. J., et al. (2010) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2010.04.006 · Cited by 2,882 · see citing works
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
O’Roak, B. J., Vives, L., Girirajan, S., Karakoc, E., Krumm, N., Coe, B. P., Levy, R., Ko, A., Lee, C., Smith, J. D., et al. (2012) · Nature · doi:10.1038/nature10989 · Cited by 2,165 · see citing works
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Sanders, S. J., Murtha, M. T., Gupta, A. R., Murdoch, J. D., Raubeson, M. J., Willsey, A. J., Ercan-Sencicek, A. G., DiLullo, N. M., Parikshak, N. N., Stein, J. L., et al. (2012) · Nature · doi:10.1038/nature10945 · Cited by 2,084 · see citing works
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Neale, B. M., Kou, Y., Liu, L., Ma’ayan, A., Samocha, K. E., Sabo, A., Lin, C.-F., Stevens, C., Wang, L.-S., Makarov, V., et al. (2012) · Nature · doi:10.1038/nature11011 · Cited by 1,734 · see citing works
De Novo Gene Disruptions in Children on the Autistic Spectrum
Iossifov, I., Ronemus, M., Levy, D., Wang, Z., Hakker, I., Rosenbaum, J., Yamrom, B., Lee, Y.-H., Narzisi, G., Leotta, A., et al. (2012) · Neuron · doi:10.1016/j.neuron.2012.04.009 · Cited by 1,446 · see citing works
Deep sequencing reveals 50 novel genes for recessive cognitive disorders
Najmabadi, H., Hu, H., Garshasbi, M., Zemojtel, T., Abedini, S. S., Chen, W., Hosseini, M., Behjati, F., Haas, S., Jamali, P., et al. (2011) · Nature · doi:10.1038/nature10423 · Cited by 965 · see citing works
A de novo paradigm for mental retardation.
Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., et al. (2010) · Nature Genetics · doi:10.1038/ng.712 · Cited by 852 · see citing works
Self-citationDe novo mutations in human genetic disease
Veltman, J. A., & Brunner, H. G. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3241 · Cited by 845 · see citing works
Self-citationWhole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy
Lupski, J. R., Reid, J. G., Gonzaga-Jauregui, C., Rio Deiros, D., Chen, D. C. Y., Nazareth, L., Bainbridge, M., Dinh, H., Jing, C., Wheeler, D. A., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa0908094 · Cited by 759 · see citing works
The epidemiology of mental retardation: Challenges and opportunities in the new millennium
Leonard, H., & Wen, X. (2002) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.10031 · Cited by 619 · see citing works
Berg, J. S., Khoury, M. J., & Evans, J. P. (2011) · Genetics in Medicine · doi:10.1097/gim.0b013e318220aaba · Cited by 489 · see citing works
Debant, A., Serra‐Pages, C., Seipel, K., O'Brien, S., Tang, M. H. Y., Park, S. H., & Streuli, M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.11.5466 · Cited by 467 · see citing works
Rauch, A. M., Hoyer, J., Guth, S., Zweier, C., Kraus, C. S., Becker, C., Zenker, M., Hüffmeier, U., Thiel, C. T., Rüschendorf, F., et al. (2006) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.31416 · Cited by 430 · see citing works
Genetic and Epigenetic Networks in Intellectual Disabilities
van Bokhoven, H. (2011) · Annual Review of Genetics · doi:10.1146/annurev-genet-110410-132512 · Cited by 382 · see citing works
Genetics of Early Onset Cognitive Impairment
Ropers, H. (2010) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-082509-141640 · Cited by 365 · see citing works
Hamdan, F. F., Gauthier, J., Araki, Y., Lin, D.-T., Yoshizawa, Y., Higashi, K., Park, A.-R., Spiegelman, D., Dobrzeniecka, S., Piton, A., et al. (2011) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2011.02.001 · Cited by 349 · see citing works
Mutations in <i>SYNGAP1</i> in Autosomal Nonsyndromic Mental Retardation
Hamdan, F. F., Gauthier, J., Spiegelman, D., Noreau, A., Yang, Y., Pellerin, S., Dobrzeniecka, S., Côté, M., Perreau-Linck, E., Carmant, L., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0805392 · Cited by 336 · see citing works
Genomics, Intellectual Disability, and Autism
Mefford, H. C., Batshaw, M. L., & Hoffman, E. P. (2012) · New England Journal of Medicine · doi:10.1056/nejmra1114194 · Cited by 329 · see citing works
Hochstenbach, R., van Binsbergen, E., Engelen, J. J. M., Nieuwint, A. W. M., Polstra, A. M., Poddighe, P. J., Ruivenkamp, C. A. L., Sikkema‐Raddatz, B., Smeets, D., & Poot, M. (2009) · European Journal of Medical Genetics · doi:10.1016/j.ejmg.2009.03.015 · Cited by 283 · see citing works
Clinical Genetic Evaluation of the Child With Mental Retardation or Developmental Delays
Moeschler, J. B., & Shevell, M. I. (2006) · PEDIATRICS · doi:10.1542/peds.2006-1006 · Cited by 246 · see citing works
Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology
Catarino, C. B., Liu, J. Y. W., Liagkouras, I., Gibbons, V. S., Labrum, R. W., Ellis, R., Woodward, C., Davis, M. B., Smith, S. J., Cross, J. H., et al. (2011) · Brain · doi:10.1093/brain/awr129 · Cited by 227 · see citing works
Sagoo, G. S., Butterworth, A. S., Sanderson, S., Shaw-Smith, C. J., Higgins, J. P. T., & Burton, H. (2009) · Genetics in Medicine · doi:10.1097/gim.0b013e318194ee8f · Cited by 220 · see citing works
Clinical Genetic Evaluation of the Child with Mental Retardation or Developmental Delays
Moeschler, J. B., & Shevell, M. I. (2014) · American Academy of Pediatrics eBooks · doi:10.1542/9781581108613-part05-clinical_genetic · Cited by 207 · see citing works
Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects
Willemsen, M. H., Vissers, L. E. L. M., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., Vries, B. B. A. D., Schoots, J., Lugtenberg, D., Hamel, B. C. J., et al. (2012) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2011-100542 · Cited by 183 · see citing works
Self-citationDiagnostic evaluation of developmental delay/mental retardation: An overview
Battaglia, A., & Carey, J. C. (2003) · American Journal of Medical Genetics Part C Seminars in Medical Genetics · doi:10.1002/ajmg.c.10015 · Cited by 154 · see citing works
Exome sequencing and the genetics of intellectual disability
Topper, S., Ober, C., & Das, S. (2011) · Clinical Genetics · doi:10.1111/j.1399-0004.2011.01720.x · Cited by 85 · see citing works
Pyruvate dehydrogenase deficiency and epilepsy
Prasad, C., Rupar, T., & Prasad, A. N. (2011) · Brain and Development · doi:10.1016/j.braindev.2011.08.003 · Cited by 71 · see citing works
Mental Retardation in Children Ages 6 to 16
Shea, S. E. (2006) · Seminars in Pediatric Neurology · doi:10.1016/j.spen.2006.09.010 · Cited by 28 · see citing works
Intellectual Disability and Autism
Bettis, J. (2016) · The SAGE Encyclopedia of Marriage, Family, and Couples Counseling · doi:10.4135/9781483369532.n264 · Cited by 28 · see citing works
The Clinical Evaluation of Patients with Mental Retardation/Intellectual Disability
Romano, C. (2010) · Monographs in human genetics · doi:10.1159/000287596 · Cited by 10 · see citing works
Retinoblastoma: Mutational mosaicism or host resistance?
Matsunaga, E., Herrmann, J., & Opitz, J. M. (1981) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320080403 · Cited by 10 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Prasad C, Rupar T, Prasad AN. Pyru- vate dehydrogenase deficiency and epi- lepsy. Brain Dev 2011;33:856-65.
Cited by
Sorted by citations
A general framework for estimating the relative pathogenicity of human genetic variants
Kircher, M., Witten, D. M., Jain, P., O'Roak, B. J., Cooper, G. M., & Shendure, J. (2014) · Nature Genetics · doi:10.1038/ng.2892 · Cited by 6,183 · see citing works
The contribution of de novo coding mutations to autism spectrum disorder
Iossifov, I., O’Roak, B. J., Sanders, S. J., Ronemus, M., Krumm, N., Levy, D., Stessman, H. A., Witherspoon, K. T., Vives, L., Patterson, K. E., et al. (2014) · Nature · doi:10.1038/nature13908 · Cited by 2,585 · see citing works
De novo mutations in schizophrenia implicate synaptic networks
Fromer, M., Pocklington, A. J., Kavanagh, D. H., Williams, H. J., Dwyer, S., Gormley, P., Georgieva, L., Rees, E., Palta, P., Ruderfer, D. M., et al. (2014) · Nature · doi:10.1038/nature12929 · Cited by 1,617 · see citing works
Prevalence and architecture of de novo mutations in developmental disorders
Study, D. D. D. (2017) · Nature · doi:10.1038/nature21062 · Cited by 1,480 · see citing works
De novo mutations in epileptic encephalopathies
Epi4K Consortium, & Epilepsy Phenome/Genome Project (2013) · Nature · doi:10.1038/nature12439 · Cited by 1,514 · see citing works
A polygenic burden of rare disruptive mutations in schizophrenia
Purcell, S. M., Moran, J. L., Fromer, M., Ruderfer, D., Solovieff, N., Roussos, P., O’Dushlaine, C., Chambert, K., Bergen, S. E., Kähler, A., et al. (2014) · Nature · doi:10.1038/nature12975 · Cited by 1,385 · see citing works
Molecular Findings Among Patients Referred for Clinical Whole-Exome Sequencing
Yang, Y., Muzny, D. M., Xia, F., Niu, Z., Person, R., Ding, Y., Ward, P., Braxton, A., Wang, M., Buhay, C., et al. (2014) · JAMA · doi:10.1001/jama.2014.14601 · Cited by 1,360 · see citing works
Guidelines for investigating causality of sequence variants in human disease
MacArthur, D. G., Manolio, T. A., Dimmock, D. P., Rehm, H. L., Shendure, J., Abecasis, G. R., Adams, D. R., Altman, R. B., Antonarakis, S. E., Ashley, E. A., et al. (2014) · Nature · doi:10.1038/nature13127 · Cited by 1,224 · see citing works
Gene expression elucidates functional impact of polygenic risk for schizophrenia
Fromer, M., Roussos, P., Sieberts, S. K., Johnson, J. S., Kavanagh, D. H., Perumal, T. M., Ruderfer, D. M., Oh, E. C., Topol, A., Shah, H. R., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4399 · Cited by 1,091 · see citing works
Large-scale discovery of novel genetic causes of developmental disorders
Study, T. D. D. D. (2015) · Nature · doi:10.1038/nature14135 · Cited by 1,124 · see citing works
Genome sequencing identifies major causes of severe intellectual disability
Gilissen, C., Hehir-Kwa, J. Y., Thung, D. T., van de Vorst, M., van Bon, B. W. M., Willemsen, M. H., Kwint, M., Janssen, I. M., Hoischen, A., Schenck, A., et al. (2014) · Nature · doi:10.1038/nature13394 · Cited by 1,125 · see citing works
Self-citationIntegrative functional genomic analyses implicate specific molecular pathways and circuits in autism
Parikshak, N. N., Luo, R., Zhang, A., Won, H., Lowe, J. K., Chandran, V., Horvath, S., & Geschwind, D. H. (2013) · Cell · doi:10.1016/j.cell.2013.10.031 · Cited by 1,039 · see citing works
Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap
Gandal, M. J., Haney, J. R., Parikshak, N. N., Leppa, V., Ramaswami, G., Hartl, C., Schork, A. J., Appadurai, V., Buil, A., Werge, T. M., et al. (2018) · Science · doi:10.1126/science.aad6469 · Cited by 1,095 · see citing works
Convergence of genes and cellular pathways dysregulated in autism spectrum disorders
Pinto, D., Delaby, E., Merico, D., Barbosa, M., Merikangas, A., Klei, L., Thiruvahindrapuram, B., Xu, X., Ziman, R., Wang, Z., et al. (2014) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2014.03.018 · Cited by 969 · see citing works
Genic Intolerance to Functional Variation and the Interpretation of Personal Genomes
Petrovski, S., Wang, Q., Heinzen, E. L., Allen, A. S., & Goldstein, D. B. (2013) · PLoS Genetics · doi:10.1371/journal.pgen.1003709 · Cited by 901 · see citing works
A framework for the interpretation of de novo mutation in human disease
Samocha, K. E., Robinson, E. B., Sanders, S. J., Stevens, C., Sabo, A., McGrath, L. M., Kosmicki, J. A., Rehnström, K., Mallick, S., Kirby, A., et al. (2014) · Nature Genetics · doi:10.1038/ng.3050 · Cited by 979 · see citing works
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2
Pejaver, V., Urresti, J., Lugo-Martinez, J., Pagel, K. A., Lin, G. N., Nam, H.-J., Mort, M., Cooper, D. N., Sebat, J., Iakoucheva, L. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-19669-x · Cited by 923 · see citing works
Coe, B. P., Witherspoon, K., Rosenfeld, J. A., van Bon, B. W. M., Vulto-van Silfhout, A. T., Bosco, P., Friend, K. L., Baker, C., Buono, S., Vissers, L. E. L. M., et al. (2014) · Nature Genetics · doi:10.1038/ng.3092 · Cited by 720 · see citing works
Self-citationGenetic studies in intellectual disability and related disorders
Vissers, L. E. L. M., Gilissen, C., & Veltman, J. A. (2016) · Nature Reviews Genetics · doi:10.1038/nrg3999 · Cited by 761 · see citing works
Self-citationTargeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., et al. (2013) · Nature Genetics · doi:10.1038/ng.2646 · Cited by 687 · see citing works
Cross-trial prediction of treatment outcome in depression: a machine learning approach
Chekroud, A. M., Zotti, R. J., Shehzad, Z., Gueorguieva, R., Johnson, M. K., Trivedi, M. H., Cannon, T. D., Krystal, J. H., & Corlett, P. R. (2016) · The Lancet Psychiatry · doi:10.1016/s2215-0366(15)00471-x · Cited by 676 · see citing works
Stessman, H. A. F., Xiong, B., Coe, B. P., Wang, T., Hoekzema, K., Fenckova, M., Kvarnung, M., Gerdts, J., Trinh, S., Cosemans, N., et al. (2017) · Nature Genetics · doi:10.1038/ng.3792 · Cited by 559 · see citing works
A Single-Cell Transcriptomic Atlas of Human Neocortical Development during Mid-gestation
Polioudakis, D., de la Torre-Ubieta, L., Langerman, J., Elkins, A. G., Shi, X., Stein, J. L., Vuong, C. K., Nichterwitz, S., Gevorgian, M., Opland, C. K., et al. (2019) · Neuron · doi:10.1016/j.neuron.2019.06.011 · Cited by 513 · see citing works
Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia
Genovese, G., Fromer, M., Stahl, E. A., Ruderfer, D. M., Chambert, K., Landén, M., Moran, J. L., Purcell, S. M., Sklar, P., Sullivan, P. F., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4402 · Cited by 444 · see citing works
Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders
Parikshak, N. N., Gandal, M. J., & Geschwind, D. H. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3934 · Cited by 430 · see citing works
Study, S. S., Singh, T., Study, I., Study, D., UK10 K Consortium, Kurki, M. I., Curtis, D., Purcell, S. M., Crooks, L., McRae, J., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4267 · Cited by 452 · see citing works
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
Lelieveld, S. H., Reijnders, M. R. F., Pfundt, R., Yntema, H. G., Kamsteeg, E.-J., de Vries, P., de Vries, B. B. A., Willemsen, M. H., Kleefstra, T., Löhner, K., et al. (2016) · Nature Neuroscience · doi:10.1038/nn.4352 · Cited by 442 · see citing works
Self-citationSequence Kernel Association Tests for the Combined Effect of Rare and Common Variants
Ionita-Laza, I., Lee, S., Makarov, V., Buxbaum, J. D., & Lin, X. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.04.015 · Cited by 433 · see citing works
High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies
Hamdan, F. F., Myers, C. T., Cossette, P., Lemay, P., Spiegelman, D., Laporte, A. D., Nassif, C., Diallo, O., Monlong, J., Cadieux-Dion, M., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.09.008 · Cited by 445 · see citing works
Next-generation diagnostics and disease-gene discovery with the Exomiser
Smedley, D., Jacobsen, J. O. B., Jäger, M., Köhler, S., Holtgrewe, M., Schubach, M., Siragusa, E., Zemojtel, T., Buske, O. J., Washington, N. L., et al. (2015) · Nature Protocols · doi:10.1038/nprot.2015.124 · Cited by 445 · see citing works
A de novo convergence of autism genetics and molecular neuroscience
Krumm, N., O’Roak, B. J., Shendure, J., & Eichler, E. E. (2014) · Trends in Neurosciences · doi:10.1016/j.tins.2013.11.005 · Cited by 423 · see citing works
De Novo Mutations in Moderate or Severe Intellectual Disability
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., et al. (2014) · PLoS Genetics · doi:10.1371/journal.pgen.1004772 · Cited by 419 · see citing works
Regional missense constraint improves variant deleteriousness prediction
Samocha, K. E., Kosmicki, J. A., Karczewski, K. J., O’Donnell-Luria, A. H., Pierce-Hoffman, E., MacArthur, D. G., Neale, B. M., & Daly, M. J. (2017) · doi:10.1101/148353 · Cited by 351 · see citing works
Large-scale genomics unveils the genetic architecture of psychiatric disorders
Gratten, J., Wray, N. R., Keller, M. C., & Visscher, P. M. (2014) · Nature Neuroscience · doi:10.1038/nn.3708 · Cited by 363 · see citing works
Somatic mutations in cerebral cortical malformations
Jamuar, S. S., Lam, A.-T. N., Kircher, M., D’Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1314432 · Cited by 392 · see citing works
A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP
Helsmoortel, C., Vulto-van Silfhout, A. T., Coe, B. P., Vandeweyer, G., Rooms, L., van den Ende, J., Schuurs-Hoeijmakers, J. H. M., Marcelis, C. L., Willemsen, M. H., Vissers, L. E. L. M., et al. (2014) · Nature Genetics · doi:10.1038/ng.2899 · Cited by 354 · see citing works
Self-citationNeurodevelopmental disease genes implicated by de novo mutation and copy number variation morbidity
Coe, B. P., Stessman, H. A. F., Sulovari, A., Geisheker, M. R., Bakken, T. E., Lake, A. M., Dougherty, J. D., Lein, E. S., Hormozdiari, F., Bernier, R. A., et al. (2019) · Nature Genetics · doi:10.1038/s41588-018-0288-4 · Cited by 330 · see citing works
Improved exome prioritization of disease genes through cross-species phenotype comparison
Robinson, P. N., Köhler, S., Oellrich, A., Sanger Mouse Genetics Project, Wang, K., Mungall, C. J., Lewis, S. E., Washington, N., Bauer, S., Seelow, D., et al. (2014) · Genome Research · doi:10.1101/gr.160325.113 · Cited by 375 · see citing works
Self-citationRecurrent de novo mutations implicate novel genes underlying simplex autism risk
O'Roak, B. J., Stessman, H. A., Boyle, E. A., Witherspoon, K. T., Martin, B., Lee, C., Vives, L., Baker, C., Hiatt, J. B., Nickerson, D. A., et al. (2014) · Nature Communications · doi:10.1038/ncomms6595 · Cited by 336 · see citing works
Kosmicki, J. A., Samocha, K. E., Howrigan, D. P., Sanders, S. J., Slowikowski, K., Lek, M., Karczewski, K. J., Cutler, D. J., Devlin, B., Roeder, K., et al. (2017) · Nature Genetics · doi:10.1038/ng.3789 · Cited by 340 · see citing works
Smedley, D., Schubach, M., Jacobsen, J. O. B., Köhler, S., Zemojtel, T., Spielmann, M., Jäger, M., Hochheiser, H., Washington, N. L., McMurry, J. A., et al. (2016) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2016.07.005 · Cited by 283 · see citing works
Exome Sequencing and the Management of Neurometabolic Disorders
Tarailo-Graovac, M., Shyr, C., Ross, C. J., Horvath, G. A., Salvarinova, R., Ye, X. C., Zhang, L.-H., Bhavsar, A. P., Lee, J. J. Y., Drögemöller, B. I., et al. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1515792 · Cited by 281 · see citing works
The discovery of integrated gene networks for autism and related disorders
Hormozdiari, F., Penn, O., Borenstein, E., & Eichler, E. E. (2015) · Genome Research · doi:10.1101/gr.178855.114 · Cited by 249 · see citing works
<i>SCN2A</i> encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures
Howell, K. B., McMahon, J. M., Carvill, G. L., Tambunan, D., Mackay, M. T., Rodriguez-Casero, V., Webster, R., Clark, D., Freeman, J. L., Calvert, S., et al. (2015) · Neurology · doi:10.1212/wnl.0000000000001926 · Cited by 255 · see citing works
Lessons learned from additional research analyses of unsolved clinical exome cases
Eldomery, M. K., Coban-Akdemir, Z., Harel, T., Rosenfeld, J. A., Gambin, T., Stray-Pedersen, A., Küry, S., Mercier, S., Lessel, D., Denecke, J., et al. (2017) · Genome Medicine · doi:10.1186/s13073-017-0412-6 · Cited by 230 · see citing works
Whole exome sequencing of suspected mitochondrial patients in clinical practice
Wortmann, S. B., Koolen, D. A., Smeitink, J. A., den van Heuvel, L., & Rodenburg, R. J. (2015) · Journal of Inherited Metabolic Disease · doi:10.1007/s10545-015-9823-y · Cited by 233 · see citing works
Self-citationDoherty, J. L., & Owen, M. J. (2014) · Genome Medicine · doi:10.1186/gm546 · Cited by 228 · see citing works
<i>SYNGAP1</i> encephalopathy: A distinctive generalized developmental and epileptic encephalopathy
Vlaskamp, D. R. M., Shaw, B. J., Burgess, R., Mei, D., Montomoli, M., Xie, H., Myers, C. T., Bennett, M. F., XiangWei, W., Williams, D., et al. (2019) · Neurology · doi:10.1212/wnl.0000000000006729 · Cited by 206 · see citing works
Coffin-Siris Syndrome and the BAF Complex: Genotype-Phenotype Study in 63 Patients
Santen, G. W. E., Aten, E., Vulto-van Silfhout, A. T., Pottinger, C., van Bon, B. W. M., van Minderhout, I. J. H. M., Snowdowne, R., van der Lans, C. A. C., Boogaard, M., Linssen, M. M. L., et al. (2013) · Human Mutation · doi:10.1002/humu.22394 · Cited by 221 · see citing works
Self-citationUnderstanding Human Glycosylation Disorders: Biochemistry Leads the Charge
Freeze, H. H. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.r112.429274 · Cited by 213 · see citing works
Loss-of-Function Variants in Schizophrenia Risk and SETD1A as a Candidate Susceptibility Gene
Takata, A., Xu, B., Ionita-Laza, I., Roos, J. L., Gogos, J. A., & Karayiorgou, M. (2014) · Neuron · doi:10.1016/j.neuron.2014.04.043 · Cited by 204 · see citing works
Delineating the <i>GRIN1</i> phenotypic spectrum: A distinct genetic NMDA receptor encephalopathy
Lemke, J. R., Geider, K., Helbig, K. L., Heyne, H. O., Schütz, H., Hentschel, J., Courage, C., Depienne, C., Nava, C., Heron, D., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002740 · Cited by 200 · see citing works
Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder
Krupp, D. R., Barnard, R. A., Duffourd, Y., Evans, S. A., Mulqueen, R. M., Bernier, R., Rivière, J.-B., Fombonne, E., & O’Roak, B. J. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.07.016 · Cited by 204 · see citing works
De Novo Coding Variants Are Strongly Associated with Tourette Disorder
Willsey, A. J., Fernandez, T. V., Yu, D., King, R. A., Dietrich, A., Xing, J., Sanders, S. J., Mandell, J. D., Huang, A. Y., Richer, P., et al. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.024 · Cited by 187 · see citing works
The nucleosome remodeling and deacetylase complex in development and disease
Basta, J., & Rauchman, M. (2015) · Translational Research · doi:10.1016/j.trsl.2014.05.003 · Cited by 191 · see citing works
Howrigan, D. P., Rose, S. A., Samocha, K. E., Fromer, M., Cerrato, F., Chen, W. J., Churchhouse, C., Chambert, K., Chandler, S. D., Daly, M. J., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0564-3 · Cited by 168 · see citing works
From Structure to Phenotype: Impact of Collagen Alterations on Human Health
Arseni, L., Lombardi, A., & Orioli, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051407 · Cited by 186 · see citing works
“Normal growth parameters and no evident dysmorphism are recorded in adults [121,122].”
BackgroundUnifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops
Mullins, C., Fishell, G., & Tsien, R. W. (2016) · Neuron · doi:10.1016/j.neuron.2016.02.017 · Cited by 167 · see citing works
De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability
Küry, S., van Woerden, G. M., Besnard, T., Proietti Onori, M., Latypova, X., Towne, M. C., Cho, M. T., Prescott, T. E., Ploeg, M. A., Sanders, S., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.10.003 · Cited by 185 · see citing works
Self-citationLightbody, G., Haberland, V., Browne, F., Taggart, L., Zheng, H., Parkes, E., & Blayney, J. K. (2019) · Briefings in Bioinformatics · doi:10.1093/bib/bby051 · Cited by 173 · see citing works
Guo, H., Wang, T., Wu, H., Long, M., Coe, B. P., Li, H., Xun, G., Ou, J., Chen, B., Duan, G., et al. (2018) · Molecular Autism · doi:10.1186/s13229-018-0247-z · Cited by 154 · see citing works
Insufficient Evidence for “Autism-Specific” Genes
Myers, S. M., Challman, T. D., Bernier, R., Bourgeron, T., Chung, W. K., Constantino, J. N., Eichler, E. E., Jacquemont, S., Miller, D. T., Mitchell, K. J., et al. (2020) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2020.04.004 · Cited by 165 · see citing works
NANS-mediated synthesis of sialic acid is required for brain and skeletal development
van Karnebeek, C. D. M., Bonafé, L., Wen, X.-Y., Tarailo-Graovac, M., Balzano, S., Royer-Bertrand, B., Ashikov, A., Garavelli, L., Mammi, I., Turolla, L., et al. (2016) · Nature Genetics · doi:10.1038/ng.3578 · Cited by 164 · see citing works
Robinson, E. B., Samocha, K. E., Kosmicki, J. A., McGrath, L., Neale, B. M., Perlis, R. H., & Daly, M. J. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1409204111 · Cited by 142 · see citing works
Prioritization of neurodevelopmental disease genes by discovery of new mutations
Hoischen, A., Krumm, N., & Eichler, E. E. (2014) · Nature Neuroscience · doi:10.1038/nn.3703 · Cited by 149 · see citing works
Self-citationAn assessment of sex bias in neurodevelopmental disorders
Polyak, A., Rosenfeld, J. A., & Girirajan, S. (2015) · Genome Medicine · doi:10.1186/s13073-015-0216-5 · Cited by 129 · see citing works
Whole exome sequencing in patients with white matter abnormalities
Vanderver, A., Simons, C., Helman, G., Crawford, J., Wolf, N. I., Bernard, G., Pizzino, A., Schmidt, J. L., Takanohashi, A., Miller, D., et al. (2016) · Annals of Neurology · doi:10.1002/ana.24650 · Cited by 145 · see citing works
Recurrent de novo mutations in neurodevelopmental disorders: properties and clinical implications
Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
Aceti, M., Creson, T. K., Vaissiere, T., Rojas, C., Huang, W.-C., Wang, Y.-X., Petralia, R. S., Page, D. T., Miller, C. A., & Rumbaugh, G. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.08.001 · Cited by 129 · see citing works
One gene, many neuropsychiatric disorders: lessons from Mendelian diseases
Zhu, X., Need, A. C., Petrovski, S., & Goldstein, D. B. (2014) · Nature Neuroscience · doi:10.1038/nn.3713 · Cited by 131 · see citing works
B56δ-related protein phosphatase 2A dysfunction identified in patients with intellectual disability
Houge, G., Haesen, D., Vissers, L. E. L. M., Mehta, S., Parker, M. J., Wright, M., Vogt, J., McKee, S., Tolmie, J. L., Cordeiro, N., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79860 · Cited by 124 · see citing works
Self-citationDiscontinuity in the genetic and environmental causes of the intellectual disability spectrum
Reichenberg, A., Cederlöf, M., McMillan, A., Trzaskowski, M., Kapra, O., Fruchter, E., Ginat, K., Davidson, M., Weiser, M., Larsson, H., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1508093112 · Cited by 115 · see citing works
Chen, Y., Huang, W.-C., Sejourne, J., Clipperton-Allen, A. E., & Page, D. T. (2015) · Journal of Neuroscience · doi:10.1523/jneurosci.5272-14.2015 · Cited by 117 · see citing works
Küry, S., Besnard, T., Ebstein, F., Khan, T. N., Gambin, T., Douglas, J., Bacino, C. A., Craigen, W. J., Sanders, S. J., Lehmann, A., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.01.003 · Cited by 110 · see citing works
Kobayashi, Y., Tohyama, J., Kato, M., Akasaka, N., Magara, S., Kawashima, H., Ohashi, T., Shiraishi, H., Nakashima, M., Saitsu, H., et al. (2016) · Brain and Development · doi:10.1016/j.braindev.2015.09.011 · Cited by 84 · see citing works
De novo variants in SETD1B are associated with intellectual disability, epilepsy and autism
Hiraide, T., Nakashima, M., Yamoto, K., Fukuda, T., Kato, M., Ikeda, H., Sugie, Y., Aoto, K., Kaname, T., Nakabayashi, K., et al. (2018) · Human Genetics · doi:10.1007/s00439-017-1863-y · Cited by 75 · see citing works
Wang, W., Corominas, R., & Lin, G. N. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00258 · Cited by 70 · see citing works
Reijnders, M. R. F., Kousi, M., van Woerden, G. M., Klein, M., Bralten, J., Mancini, G. M. S., van Essen, T., Proietti-Onori, M., Smeets, E. E. J., van Gastel, M., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-00933-6 · Cited by 76 · see citing works
Vissers, L. E., Bonetti, M., Paardekooper Overman, J., Nillesen, W. M., Frints, S. G. M., de Ligt, J., Zampino, G., Justino, A., Machado, J. C., Schepens, M., et al. (2015) · European Journal of Human Genetics · doi:10.1038/ejhg.2014.115 · Cited by 75 · see citing works
Self-citationMutations in <i>HECW2</i> are associated with intellectual disability and epilepsy
Halvardson, J., Zhao, J. J., Zaghlool, A., Wentzel, C., Georgii-Hemming, P., Månsson, E., Ederth Sävmarker, H., Brandberg, G., Soussi Zander, C., Thuresson, A.-C., et al. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2016-103814 · Cited by 71 · see citing works
Cappi, C., Brentani, H., Lima, L., Sanders, S. J., Zai, G., Diniz, B. J., Reis, V. N. S., Hounie, A. G., Conceição do Rosário, M., Mariani, D., et al. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.30 · Cited by 71 · see citing works
Cohen, S. M., Suutari, B., He, X., Wang, Y., Sanchez, S., Tirko, N. N., Mandelberg, N. J., Mullins, C., Zhou, G., Wang, S., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04705-8 · Cited by 67 · see citing works
Smogavec, M., Cleall, A., Hoyer, J., Lederer, D., Nassogne, M.-C., Palmer, E. E., Deprez, M., Benoit, V., Maystadt, I., Noakes, C., et al. (2016) · Journal of Medical Genetics · doi:10.1136/jmedgenet-2016-103880 · Cited by 56 · see citing works
Shoubridge, C., Harvey, R. J., & Dudding-Byth, T. (2019) · Human Mutation · doi:10.1002/humu.23670 · Cited by 44 · see citing works
McRae, J. F., Clayton, S., Fitzgerald, T. W., Kaplanis, J., Prigmore, E., Rajan, D., Sifrim, A., Aitken, S., Akawi, N., Alvi, M., et al. (2016) · doi:10.1101/049056 · Cited by 30 · see citing works
Juliá-Palacios, N., Olivella, M., Sigatullina Bondarenko, M., Ibáñez-Micó, S., Muñoz-Cabello, B., Alonso-Luengo, O., Soto-Insuga, V., García-Navas, D., Cuesta-Herraiz, L., Andreo-Lillo, P., et al. (2024) · Brain · doi:10.1093/brain/awae041 · Cited by 36 · see citing works
Platzer, K., Cogné, B., Hague, J., Marcelis, C. L., Mitter, D., Oberndorff, K., Park, S., Ploos van Amstel, H. K., Simonic, I., van der Smagt, J. J., et al. (2018) · Annals of Neurology · doi:10.1002/ana.25278 · Cited by 29 · see citing works
Molecular subtyping and improved treatment of neurodevelopmental disease
Stessman, H. A. F., Turner, T. N., & Eichler, E. E. (2016) · Genome Medicine · doi:10.1186/s13073-016-0278-z · Cited by 25 · see citing works
Mozzi, A., Forni, D., Cagliani, R., Pozzoli, U., Clerici, M., & Sironi, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-06440-4 · Cited by 19 · see citing works
Cuinat, S., Bézieau, S., Deb, W., Mercier, S., Vignard, V., Isidor, B., Küry, S., & Ebstein, F. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2023.101130 · Cited by 10 · see citing works
Satterstrom, F. K., Kosmicki, J. A., Wang, J., Breen, M. S., De Rubeis, S., An, J.-Y., Peng, M., Collins, R., Grove, J., Klei, L., et al. (2018) · doi:10.1101/484113 · Cited by 2,323 · see citing works
“Unsurprisingly, many ASD 14 genes are also associated with NDD (22-26).”
Background
- Authors
- de Ligt, J., Willemsen, M. H., van Bon, B. W. M., Kleefstra, T., Yntema, H. G., Kroes, T., Vulto-van Silfhout, A. T., Koolen, D. A., de Vries, P., Gilissen, C., del Rosario, M., Hoischen, A., Scheffer, H., de Vries, B. B. A., Brunner, H. G., Veltman, J. A., & Vissers, L. E. L. M.
- Affiliations
- Radboud University Nijmegen (NL)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-11-15
- Volume
- 367
- Issue
- 20
- Pages
- 1921-1929
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2115558586
- Cited by
- 1,546
- References
- 31
- Citations by year
- 2026: 37 · 2025: 61 · 2024: 88 · 2023: 71 · 2022: 97 · 2021: 101 · 2020: 108 · 2019: 111 · 2018: 151 · 2017: 173 · 2016: 149 · 2015: 133 · 2014: 163 · 2013: 93 · 2012: 6
- FWCI
- 74.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, other-oa)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Keywords
- intellectual disability, exome sequencing, de novo mutations, X-linked mutations, autosomal recessive mutation, candidate genes, diagnostic yield, genetic heterogeneity, molecular diagnosis
- MeSH terms
- Adolescent, Child, Female, Genes, Recessive, Humans, Male, Intellectual Disability, Mutation, Sequence Analysis, DNA, Genetic Diseases, X-Linked, Genes, X-Linked, Young Adult, Exome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
