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Phenotypes
Original research
Refining nosology by modelling variation among facial phenotypes: the RASopathies
  1. Harold Matthews1,2,3,
  2. Michiel Vanneste1,2,
  3. Kaitlin Katsura4,
  4. David Aponte5,
  5. Michael Patton6,
  6. Peter Hammond1,
  7. Gareth Baynam7,8,9,10,
  8. Richard Spritz11,
  9. Ophir D Klein4,
  10. Benedikt Hallgrimsson5,
  11. Hilde Peeters1,
  12. Peter Claes1,2,3,12
  1. 1 Department of Human Genetics, KU Leuven, Leuven, Flemish Brabant, Belgium
  2. 2 Medical Imaging Research Center, UZ Leuven, Leuven, Flemish Brabant, Belgium
  3. 3 Facial Sciences Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
  4. 4 Program in Craniofacial Biology, Departments of Orofacial Sciences and Pediatrics, and Institute for Human Genetics, University of California San Francisco, San Francisco, California, USA
  5. 5 Department of Cell Biology and Anatomy, University of Calgary Cumming School of Medicine, Calgary, Alberta, Canada
  6. 6 Medical Genetics Unit, St George's University of London, London, UK
  7. 7 Western Australian Register of Developmental Anomalies, King Edward Memorial Hospital, Perth, Western Australia, Australia
  8. 8 Telethon Kids Institute and Division of Paediatrics, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia
  9. 9 School of Earth and Planetary Sciences, Faculty of Science and Engineering, Curtin University, Perth, Western Australia, Australia
  10. 10 Faculty of Medicine, Notre Dame University, Fremantle, Western Australia, Australia
  11. 11 Department of Paediatrics, University of Colorado Denver School of Medicine, Aurora, Colorado, USA
  12. 12 Department of Electrical Engineering ESAT/PSI, KU Leuven, Leuven, Flemish Brabant, Belgium
  1. Correspondence to Professor Peter Claes, Medical Imaging Research Center, UZ Leuven, Leuven, Belgium; peter.claes{at}kuleuven.be

Abstract

Background In clinical genetics, establishing an accurate nosology requires analysis of variations in both aetiology and the resulting phenotypes. At the phenotypic level, recognising typical facial gestalts has long supported clinical and molecular diagnosis; however, the objective analysis of facial phenotypic variation remains underdeveloped. In this work, we propose exploratory strategies for assessing facial phenotypic variation within and among clinical and molecular disease entities and deploy these techniques on cross-sectional samples of four RASopathies: Costello syndrome (CS), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC) and neurofibromatosis type 1 (NF1).

Methods From three-dimensional dense surface scans, we model the typical phenotypes of the four RASopathies as average ‘facial signatures’ and assess individual variation in terms of direction (what parts of the face are affected and in what ways) and severity of the facial effects. We also derive a metric of phenotypic agreement between the syndromes and a metric of differences in severity along similar phenotypes.

Results CFC shows a relatively consistent facial phenotype in terms of both direction and severity that is similar to CS and NS, consistent with the known difficulty in discriminating CFC from NS based on the face. CS shows a consistent directional phenotype that varies in severity. Although NF1 is highly variable, on average, it shows a similar phenotype to CS.

Conclusions We established an approach that can be used in the future to quantify variations in facial phenotypes between and within clinical and molecular diagnoses to objectively define and support clinical nosologies.

  • Phenotype
  • Methods
  • Diagnosis

Data availability statement

Data are available in a public, open access repository. The data from the FaceBase repository (https://doi.org/10.25550/1WWC) are available to researchers pending an approved data access request. Data from other sources were collected without approval for broad data sharing and are not publicly available.

https://doi.org/10.1136/jmedgenet-2021-108366

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    Data availability statement

    Data are available in a public, open access repository. The data from the FaceBase repository (https://doi.org/10.25550/1WWC) are available to researchers pending an approved data access request. Data from other sources were collected without approval for broad data sharing and are not publicly available.

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    Footnotes

    • Contributors HM designed and implemented all analyses with input from PC and BH. HM wrote the first draft of the manuscript. MV, KK, DA, MP, PH, GB, RS, ODK, BH and HP revised the manuscript, providing insights on the clinical and biological context of the work. KK, DA, MP, PH, GB, RS, ODK and BH were responsible for data collection and recruitment. HM is responsible for the overall content as the guarantor.

    • Funding This work was supported by the research fund KU Leuven (BOF-C1, C14/15/081 & C14/20/081; PC); NIH-NIDCR (U01DE024440; RS, ODK and BH); the Research Programme of the Research Foundation Flanders (Belgium) (FWO, G078518N; PC). HP is a senior clinical investigator of the FWO (18B1521N).

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.