Evidence for 28 genetic disorders discovered by combining healthcare and research data

doi:10.1038/s41586-020-2832-5

. 2020 Oct;586(7831):757-762.

doi: 10.1038/s41586-020-2832-5. Epub 2020 Oct 14.

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Joanna Kaplanis^#¹, Kaitlin E Samocha^#¹, Laurens Wiel^#^{2

3}, Zhancheng Zhang^#⁴, Kevin J Arvai⁴, Ruth Y Eberhardt¹, Giuseppe Gallone¹, Stefan H Lelieveld², Hilary C Martin¹, Jeremy F McRae¹, Patrick J Short¹, Rebecca I Torene⁴, Elke de Boer⁵, Petr Danecek¹, Eugene J Gardner¹, Ni Huang¹, Jenny Lord^{1

6}, Iñigo Martincorena¹, Rolph Pfundt⁵, Margot R F Reijnders^{2

7}, Alison Yeung^{8

9}, Helger G Yntema⁵; Deciphering Developmental Disorders Study; Lisenka E L M Vissers⁵, Jane Juusola⁴, Caroline F Wright¹⁰, Han G Brunner^{5

7

11

12}, Helen V Firth^{1

13}, David R FitzPatrick¹⁴, Jeffrey C Barrett¹, Matthew E Hurles¹⁵, Christian Gilissen², Kyle Retterer⁴

Collaborators, Affiliations

Collaborators

Deciphering Developmental Disorders Study:
Silvia Borras, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross, Stephen Tennant, Tabib Dabir, Deirdre Donnelly, Mervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J Morrison, Gillian Rea, Fiona Stewart, Trevor Cole, Nicola Cooper, Lisa Cooper-Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O'Driscoll, Kai-Ren Ong, Deborah Osio, Nicola Ragge, Sarah Turton, Julie Vogt, Denise Williams, Simon Bodek, Alan Donaldson, Alison Hills, Karen Low, Ruth Newbury-Ecob, Andrew M Norman, Eileen Roberts, Ingrid Scurr, Sarah Smithson, Madeleine Tooley, Steve Abbs, Ruth Armstrong, Carolyn Dunn, Simon Holden, Soo-Mi Park, Joan Paterson, Lucy Raymond, Evan Reid, Richard Sandford, Ingrid Simonic, Marc Tischkowitz, Geoff Woods, Lisa Bradley, Joanne Comerford, Andrew Green, Sally Lynch, Shirley McQuaid, Brendan Mullaney, Jonathan Berg, David Goudie, Eleni Mavrak, Joanne McLean, Catherine McWilliam, Eleanor Reavey, Tara Azam, Elaine Cleary, Andrew Jackson, Wayne Lam, Anne Lampe, David Moore, Mary Porteous, Emma Baple, Júlia Baptista, Carole Brewer, Bruce Castle, Emma Kivuva, Martina Owens, Julia Rankin, Charles Shaw-Smith, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Therese Bradley, Rosemarie Davidson, Carol Gardiner, Shelagh Joss, Esther Kinning, Cheryl Longman, Ruth McGowan, Victoria Murday, Daniela Pilz, Edward Tobias, Margo Whiteford, Nicola Williams, Angela Barnicoat, Emma Clement, Francesca Faravelli, Jane Hurst, Lucy Jenkins, Wendy Jones, V K Ajith Kumar, Melissa Lees, Sam Loughlin, Alison Male, Deborah Morrogh, Elisabeth Rosser, Richard Scott, Louise Wilson, Ana Beleza, Charu Deshpande, Frances Flinter, Muriel Holder, Melita Irving, Louise Izatt, Dragana Josifova, Shehla Mohammed, Aneta Molenda, Leema Robert, Wendy Roworth, Deborah Ruddy, Mina Ryten, Shu Yau, Christopher Bennett, Moira Blyth, Jennifer Campbell, Andrea Coates, Angus Dobbie, Sarah Hewitt, Emma Hobson, Eilidh Jackson, Rosalyn Jewell, Alison Kraus, Katrina Prescott, Eamonn Sheridan, Jenny Thomson, Kirsty Bradshaw, Abhijit Dixit, Jacqueline Eason, Rebecca Haines, Rachel Harrison, Stacey Mutch, Ajoy Sarkar, Claire Searle, Nora Shannon, Abid Sharif, Mohnish Suri, Pradeep Vasudevan, Natalie Canham, Ian Ellis, Lynn Greenhalgh, Emma Howard, Victoria Stinton, Andrew Swale, Astrid Weber, Siddharth Banka, Catherine Breen, Tracy Briggs, Emma Burkitt-Wright, Kate Chandler, Jill Clayton-Smith, Dian Donnai, Sofia Douzgou, Lorraine Gaunt, Elizabeth Jones, Bronwyn Kerr, Claire Langley, Kay Metcalfe, Audrey Smith, Ronnie Wright, David Bourn, John Burn, Richard Fisher, Steve Hellens, Alex Henderson, Tara Montgomery, Miranda Splitt, Volker Straub, Michael Wright, Simon Zwolinski, Zoe Allen, Birgitta Bernhard, Angela Brady, Claire Brooks, Louise Busby, Virginia Clowes, Neeti Ghali, Susan Holder, Rita Ibitoye, Emma Wakeling, Edward Blair, Jenny Carmichael, Deirdre Cilliers, Susan Clasper, Richard Gibbons, Usha Kini, Tracy Lester, Andrea Nemeth, Joanna Poulton, Sue Price, Debbie Shears, Helen Stewart, Andrew Wilkie, Shadi Albaba, Duncan Baker, Meena Balasubramanian, Diana Johnson, Michael Parker, Oliver Quarrell, Alison Stewart, Josh Willoughby, Charlene Crosby, Frances Elmslie, Tessa Homfray, Huilin Jin, Nayana Lahiri, Sahar Mansour, Karen Marks, Meriel McEntagart, Anand Saggar, Kate Tatton-Brown, Rachel Butler, Angus Clarke, Sian Corrin, Andrew Fry, Arveen Kamath, Emma McCann, Hood Mugalaasi, Caroline Pottinger, Annie Procter, Julian Sampson, Francis Sansbury, Vinod Varghese, Diana Baralle, Alison Callaway, Emma J Cassidy, Stacey Daniels, Andrew Douglas, Nicola Foulds, David Hunt, Mira Kharbanda, Katherine Lachlan, Catherine Mercer, Lucy Side, I Karen Temple, Diana Wellesley

Affiliations

¹ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
² Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ GeneDx, Gaithersburg, MD, USA.
⁵ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
⁷ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁸ Victorian Clinical Genetics Services, Melbourne, Victoria, Australia.
⁹ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
¹⁰ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK.
¹¹ GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
¹² MHENS School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
¹³ East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁵ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. meh@sanger.ac.uk.

^# Contributed equally.

PMID: 33057194
PMCID: PMC7116826
DOI: 10.1038/s41586-020-2832-5

Evidence for 28 genetic disorders discovered by combining healthcare and research data

Joanna Kaplanis et al. Nature. 2020 Oct.

. 2020 Oct;586(7831):757-762.

doi: 10.1038/s41586-020-2832-5. Epub 2020 Oct 14.

Authors

Collaborators

Deciphering Developmental Disorders Study:
Silvia Borras, Caroline Clark, John Dean, Zosia Miedzybrodzka, Alison Ross, Stephen Tennant, Tabib Dabir, Deirdre Donnelly, Mervyn Humphreys, Alex Magee, Vivienne McConnell, Shane McKee, Susan McNerlan, Patrick J Morrison, Gillian Rea, Fiona Stewart, Trevor Cole, Nicola Cooper, Lisa Cooper-Charles, Helen Cox, Lily Islam, Joanna Jarvis, Rebecca Keelagher, Derek Lim, Dominic McMullan, Jenny Morton, Swati Naik, Mary O'Driscoll, Kai-Ren Ong, Deborah Osio, Nicola Ragge, Sarah Turton, Julie Vogt, Denise Williams, Simon Bodek, Alan Donaldson, Alison Hills, Karen Low, Ruth Newbury-Ecob, Andrew M Norman, Eileen Roberts, Ingrid Scurr, Sarah Smithson, Madeleine Tooley, Steve Abbs, Ruth Armstrong, Carolyn Dunn, Simon Holden, Soo-Mi Park, Joan Paterson, Lucy Raymond, Evan Reid, Richard Sandford, Ingrid Simonic, Marc Tischkowitz, Geoff Woods, Lisa Bradley, Joanne Comerford, Andrew Green, Sally Lynch, Shirley McQuaid, Brendan Mullaney, Jonathan Berg, David Goudie, Eleni Mavrak, Joanne McLean, Catherine McWilliam, Eleanor Reavey, Tara Azam, Elaine Cleary, Andrew Jackson, Wayne Lam, Anne Lampe, David Moore, Mary Porteous, Emma Baple, Júlia Baptista, Carole Brewer, Bruce Castle, Emma Kivuva, Martina Owens, Julia Rankin, Charles Shaw-Smith, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Therese Bradley, Rosemarie Davidson, Carol Gardiner, Shelagh Joss, Esther Kinning, Cheryl Longman, Ruth McGowan, Victoria Murday, Daniela Pilz, Edward Tobias, Margo Whiteford, Nicola Williams, Angela Barnicoat, Emma Clement, Francesca Faravelli, Jane Hurst, Lucy Jenkins, Wendy Jones, V K Ajith Kumar, Melissa Lees, Sam Loughlin, Alison Male, Deborah Morrogh, Elisabeth Rosser, Richard Scott, Louise Wilson, Ana Beleza, Charu Deshpande, Frances Flinter, Muriel Holder, Melita Irving, Louise Izatt, Dragana Josifova, Shehla Mohammed, Aneta Molenda, Leema Robert, Wendy Roworth, Deborah Ruddy, Mina Ryten, Shu Yau, Christopher Bennett, Moira Blyth, Jennifer Campbell, Andrea Coates, Angus Dobbie, Sarah Hewitt, Emma Hobson, Eilidh Jackson, Rosalyn Jewell, Alison Kraus, Katrina Prescott, Eamonn Sheridan, Jenny Thomson, Kirsty Bradshaw, Abhijit Dixit, Jacqueline Eason, Rebecca Haines, Rachel Harrison, Stacey Mutch, Ajoy Sarkar, Claire Searle, Nora Shannon, Abid Sharif, Mohnish Suri, Pradeep Vasudevan, Natalie Canham, Ian Ellis, Lynn Greenhalgh, Emma Howard, Victoria Stinton, Andrew Swale, Astrid Weber, Siddharth Banka, Catherine Breen, Tracy Briggs, Emma Burkitt-Wright, Kate Chandler, Jill Clayton-Smith, Dian Donnai, Sofia Douzgou, Lorraine Gaunt, Elizabeth Jones, Bronwyn Kerr, Claire Langley, Kay Metcalfe, Audrey Smith, Ronnie Wright, David Bourn, John Burn, Richard Fisher, Steve Hellens, Alex Henderson, Tara Montgomery, Miranda Splitt, Volker Straub, Michael Wright, Simon Zwolinski, Zoe Allen, Birgitta Bernhard, Angela Brady, Claire Brooks, Louise Busby, Virginia Clowes, Neeti Ghali, Susan Holder, Rita Ibitoye, Emma Wakeling, Edward Blair, Jenny Carmichael, Deirdre Cilliers, Susan Clasper, Richard Gibbons, Usha Kini, Tracy Lester, Andrea Nemeth, Joanna Poulton, Sue Price, Debbie Shears, Helen Stewart, Andrew Wilkie, Shadi Albaba, Duncan Baker, Meena Balasubramanian, Diana Johnson, Michael Parker, Oliver Quarrell, Alison Stewart, Josh Willoughby, Charlene Crosby, Frances Elmslie, Tessa Homfray, Huilin Jin, Nayana Lahiri, Sahar Mansour, Karen Marks, Meriel McEntagart, Anand Saggar, Kate Tatton-Brown, Rachel Butler, Angus Clarke, Sian Corrin, Andrew Fry, Arveen Kamath, Emma McCann, Hood Mugalaasi, Caroline Pottinger, Annie Procter, Julian Sampson, Francis Sansbury, Vinod Varghese, Diana Baralle, Alison Callaway, Emma J Cassidy, Stacey Daniels, Andrew Douglas, Nicola Foulds, David Hunt, Mira Kharbanda, Katherine Lachlan, Catherine Mercer, Lucy Side, I Karen Temple, Diana Wellesley

Affiliations

¹ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
² Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Centre for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ GeneDx, Gaithersburg, MD, USA.
⁵ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁶ Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK.
⁷ Department of Clinical Genetics, Maastricht University Medical Centre, Maastricht, The Netherlands.
⁸ Victorian Clinical Genetics Services, Melbourne, Victoria, Australia.
⁹ Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
¹⁰ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon & Exeter Hospital, Exeter, UK.
¹¹ GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
¹² MHENS School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.
¹³ East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁴ MRC Human Genetics Unit, MRC IGMM, University of Edinburgh, Western General Hospital, Edinburgh, UK.
¹⁵ Human Genetics Programme, Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. meh@sanger.ac.uk.

^# Contributed equally.

PMID: 33057194
PMCID: PMC7116826
DOI: 10.1038/s41586-020-2832-5

Abstract

De novo mutations in protein-coding genes are a well-established cause of developmental disorders¹. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations^1,2. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent-offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders.

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Conflict of interest statement

Competing interests

Z.Z., K.J.A., R.I.T., J.J., and K.R. are employees of GeneDx. J.J. and K.R. are shareholders of OPKO. M.E.H. is a co-founder of, consultant to, and holds shares in, Congenica Ltd, a genetics diagnostic company.

Figures

**Extended Data Figure 1. Exploring the remaining number of DD genes.**
(a) Number of significant genes from downsampling full cohort and running DeNovoWEST’s enrichment test. (b) Results from modelling the likelihood of the observed distribution of *de novo* PTV mutations. This model varies the numbers of remaining haploinsufficient (HI) DD genes and PTV enrichment in those remaining genes. The 50% credible interval is shown in red and the 90% credible interval is shown in orange. Note that the median PTV enrichment in genes that are significant and known to operate via a loss-of-function mechanism (shown with an arrow) is 39.7.

**Figure 1. Results of DeNovoWEST analysis.**
(a) Comparison of p-values using the new method (DeNovoWEST) versus the previous method (mupit), run on the full cohort. Dashed lines indicate the threshold for genome-wide significance (one sided, Bonferroni correction). Point size is proportional to the number of nonsynonymous DNMs in our cohort (nsyn). The number of genes that fall into each quadrant are annotated. (b) The number of missense and PTV DNMs in the novel genes. Point size is proportional to the log₁₀(-p-value) from analysis of the undiagnosed subset. Point colour corresponds to which test p-value was more significant: non-synonymous enrichment test in blue (pEnrich), missense enrichment and clustering test in red (pMEC). (c) The distribution of significant p-values from analysis of the undiagnosed subset for discordant and novel genes; p-values for consensus genes come from the full cohort analysis. The number of genes in each p-value bin is coloured by diagnostic gene group (n = 285 significant genes; one-sided p-values, Bonferroni corrected). Green represents the remaining fraction of cases expected to have a pathogenic *de novo* coding mutation and grey is the fraction of cases that are likely to be explained by other factors. (d) The fraction of cases (n = 31,058) with a nonsynonymous mutation in each diagnostic gene group. (e) The fraction of cases with a nonsynonymous mutation in each diagnostic gene group split by sex (n = 13,636 female and 17,422 male). In all panels, black, blue and orange represents consensus, discordant and novel genes respectively.

**Figure 2. Properties of novel genes.**
(a) The phenotypic similarity of patients with DNMs in novel and consensus genes. Random phenotypic similarity was calculated from random pairs of patients. Cases with DNMs in the same novel gene were less phenotypically similar than cases with DNMs in the same consensus gene (p = 2.3 × 10^-11, two-sided Wilcoxon rank-sum test). (b) Comparison of properties of consensus (n = 380) and novel (n = 28) DD genes known to be differential between consensus and non-DD genes (95% bootstrapped confidence intervals shown).

**Figure 3. Factors influencing power.**
(a) PTV mutability is significantly lower (p = 4.6 × 10^-68, two-sided Wilcox rank sum test) in genes that are not significantly DD-associated (blue) than in DD-associated genes (red). Median depicted with a black horizontal line. (b) Distribution of PTV enrichment in significant, likely haploinsufficient, genes by category (118 consensus, 23 discordant, 8 novel genes). Lower and upper hinges correspond to first and third quantiles. Median depicted by a horizontal grey line. The upper and lower whiskers extend 1.5 times the inter-quartile range. (c) Comparison of PTV enrichment in our cohort vs the PTV to synonymous ratio in gnomAD, for genes that are significantly PTV-enriched in our cohort (without variant weighting; n = 156 genes). PTV enrichment bins labelled with log10(enrichment). Dashed line indicates regression. Confidence intervals are 95% of the rate ratio. (d) Overall PTV enrichment across genes grouped by likelihood of presenting with a structural malformation on prenatal ultrasound (145 low, 65 medium, 6 low genes). PTV enrichment is significantly higher for genes with a low likelihood compared to other genes (p = 4.6 × 10^-5, two-sided Poisson test). Poisson 95% confidence intervals shown.

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References

1. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–438. - PMC - PubMed
1. Martin HC, et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science. 2018;362:1161–1164. - PMC - PubMed
1. Kircher M, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315. - PMC - PubMed
1. Samocha KE, et al. Regional missense constraint improves variant deleteriousness prediction. bioRxiv. 2017 doi: 10.1101/148353. 148353. - DOI
1. Kosmicki JA, et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017;49:504–510. - PMC - PubMed

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[1] Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–438. - PMC - PubMed

[2] Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542:433–438. - PMC - PubMed

[3] Martin HC, et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science. 2018;362:1161–1164. - PMC - PubMed

[4] Martin HC, et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science. 2018;362:1161–1164. - PMC - PubMed

[5] Kircher M, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315. - PMC - PubMed

[6] Kircher M, et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–315. - PMC - PubMed

[7] Samocha KE, et al. Regional missense constraint improves variant deleteriousness prediction. bioRxiv. 2017 doi: 10.1101/148353. 148353. - DOI

[8] Samocha KE, et al. Regional missense constraint improves variant deleteriousness prediction. bioRxiv. 2017 doi: 10.1101/148353. 148353. - DOI

[9] Kosmicki JA, et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017;49:504–510. - PMC - PubMed

[10] Kosmicki JA, et al. Refining the role of de novo protein-truncating variants in neurodevelopmental disorders by using population reference samples. Nat Genet. 2017;49:504–510. - PMC - PubMed

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Evidence for 28 genetic disorders discovered by combining healthcare and research data

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Evidence for 28 genetic disorders discovered by combining healthcare and research data

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