Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios1,2. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

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We thank the families for their participation and patience. We are grateful to the Exome Aggregation Consortium for making their data available. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the UK Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the UK Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South Research Ethics Committee and GEN/284/12, granted by the Republic of Ireland Research Ethics Committee). The research team acknowledges the support of the National Institutes for Health Research, through the Comprehensive Clinical Research Network. The authors wish to thank the Sanger Mouse Genetics Project for generating and providing mouse phenotyping information, N. Karp for statistical input on the mouse data and V. Narasimhan for making the bcftools roh algorithm available. D.R.F. is funded through an MRC Human Genetics Unit program grant to the University of Edinburgh. Work on the Mmp21-mutant mouse models was supported by US National Institutes of Health grant U01-HL098180 to C.W.L. V.P. was funded by a fellowship from the DFG German Research Foundation.

Author information

Author notes

    • Nadia Akawi
    •  & Jeremy McRae

    These authors contributed equally to this work.

    • David R FitzPatrick
    •  & Matthew E Hurles

    These authors jointly supervised this work.


  1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Nadia Akawi
    • , Jeremy McRae
    • , Stephen Clayton
    • , Tomas W Fitzgerald
    • , Sebastian S Gerety
    • , Wendy D Jones
    • , Daniel King
    • , Chris Lelliott
    • , Jenny Lord
    • , Virginia Piombo
    • , Elena Prigmore
    • , Diana Rajan
    • , Alejandro Sifrim
    • , Ganesh J Swaminathan
    • , Caroline F Wright
    • , Jeffrey C Barrett
    •  & Matthew E Hurles
  2. Medical Research Council (MRC) Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine (IGMM), University of Edinburgh, Western General Hospital, Edinburgh, UK.

    • Morad Ansari
    •  & David R FitzPatrick
  3. Sheffield Regional Genetics Services, Sheffield Children's National Health Service (NHS) Trust, Western Bank, Sheffield, UK.

    • Meena Balasubramanian
  4. Yorkshire Regional Genetics Service, Leeds Teaching Hospitals NHS Trust, Department of Clinical Genetics, Chapel Allerton Hospital, Leeds, UK.

    • Moira Blyth
    • , Emma Hobson
    •  & Audrey Smith
  5. North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.

    • Angela F Brady
  6. West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham, UK.

    • Trevor Cole
    • , Dominic McMullan
    •  & James Whitworth
  7. South East Thames Regional Genetics Centre, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, London, UK.

    • Charu Deshpande
  8. Wessex Clinical Genetics Service, University Hospital Southampton, Princess Anne Hospital, Southampton, UK.

    • Nicola Foulds
  9. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK.

    • Nicola Foulds
  10. Faculty of Medicine, University of Southampton, Southampton, UK.

    • Nicola Foulds
  11. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

    • Richard Francis
    • , George Gabriel
    • , Nikolai Klena
    •  & Cecilia W Lo
  12. Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Institute of Human Genetics, International Centre for Life, Newcastle upon Tyne, UK.

    • Judith Goodship
  13. West of Scotland Regional Genetics Service, NHS Greater Glasgow and Clyde, Institute of Medical Genetics, Yorkhill Hospital, Glasgow, UK.

    • Shelagh Joss
    •  & Mary O'Regan
  14. North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London, UK.

    • Ajith Kumar
    • , Melissa Lees
    •  & Elisabeth Rosser
  15. Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon and Exeter Hospital (Heavitree), Exeter, UK.

    • Deborah Osio
    •  & Peter Turnpenny
  16. East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.

    • Helen V Firth


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    A full list of members appears in the Supplementary Note.


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N.A., J.M., S.C., T.W.F., W.D.J., D.K., J.L., A. Sifrim, J.C.B., D.R.F. and M.E.H. developed analytical methods and/or analyzed human genotype and phenotype data. M. Blyth, A.F.B., M. Balasubramanian, T.C., C.D., N.F., J.G., E.H., S.J., A.K., M.L., M.O'R., D.O., E.R., A. Smith, P.T. and J.W. phenotyped patients. R.F., G.G., S.S.G., N.K., C.L., V.P. and C.W.L. generated and analyzed model organism data. M.A., D.M., E.P. and D.R. performed validation experiments. G.J.S. performed protein structure analysis. C.F.W., H.V.F., J.C.B., D.R.F. and M.E.H. supervised the experimental and analytical work. M.E.H., D.R.F., N.A., J.M. and C.W.L. wrote the manuscript. D.R.F. and M.E.H. jointly supervised the project.

Competing interests

M.E.H. is a consultant for and shareholder in Congenica, Ltd, which provides genetic diagnostic services.

Corresponding author

Correspondence to Matthew E Hurles.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7, Supplementary Tables 1, 2 and 4, and Supplementary Note.

Excel files

  1. 1.

    Supplementary Table 3

    Clinical data for four novel recessive genes.


  1. 1.

    Ciliary motility in the Mmp21 Miri mutant.

    Videomicroscopy of the embryonic node from an Mmp21 Miri mutant shows robust ciliary motility and leftward fluid flow similar to that seen in the embryonic node of a wild-type littermate control. Flow videos are shown at 200% the speed of real time to facilitate the visualization of bead movement, while cilia motion videos are shown at 15% the speed of real time to allow for better visualization of nodal ciliary motion.

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