Abstract

Au–Kline syndrome (AKS, OMIM 616580) is a multiple malformation syndrome, first reported in 2015, associated with intellectual disability. AKS has been associated with de novo loss-of-function variants in HNRNPK (heterogeneous ribonucleoprotein K), and to date, only four of these patients have been described in the literature. Recently, an additional patient with a missense variant in HNRNPK was also reported. These patients have striking facial dysmorphic features, including long palpebral fissures, ptosis, deeply grooved tongue, broad nose, and down-turned mouth. Patients frequently also have skeletal and connective tissue anomalies, craniosynostosis, congenital heart malformations, and renal anomalies. In this report, we describe six new patients and review the clinical information on all reported AKS patients, further delineating the phenotype of AKS. There are now a total of 9 patients with de novo loss-of-function variants in HNRNPK, one individual with a de novo missense variant in addition to 3 patients with de novo deletions of 9q21.32 that encompass HNRNPK. While there is considerable overlap between AKS and Kabuki syndrome (KS), these additional patients demonstrate that AKS does have a distinct facial gestalt and phenotype that can be differentiated from KS. This growing AKS patient cohort also informs an emerging approach to management and health surveillance for these patients.

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Acknowledgements

We would like to thank the patients and their families for their participation and support. We would also like to acknowledge the help and support of Marina Kerr, Lukas Lange, Alistair Pagnamenta, Jenny Taylor, and David Keays. We would also like to thank Taila Hartley (Clinical Coordinator) and Chandree Beaulieu (Project Manager) at the Children’s Hospital of Eastern Ontario Research Institute for their contribution to the infrastructure of Care4Rare. Finally, we would like to thank Care4Rare Consortium: ‘Enhanced Care for Rare Genetic Diseases in Canada’; Gene Discovery Steering Committee—Kym Boycott (lead; University of Ottawa), Alex MacKenzie (co-lead; University of Ottawa), Jacek Majewski (McGill University), Michael Brudno (University of Toronto), Dennis Bulman (University of Ottawa), David Dyment (University of Ottawa).

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Author notes

  1. These authors contributed equally: Antonie D. Kline, A. Micheil Innes.

Affiliations

  1. Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Calgary, AB, Canada

    • P. Y. Billie Au
    • , Jillian S. Parboosingh
    •  & A. Micheil Innes
  2. Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada

    • P. Y. Billie Au
    • , Caitlin Goedhart
    • , Jillian S. Parboosingh
    •  & A. Micheil Innes
  3. Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD, USA

    • Marcia Ferguson
    •  & Antonie D. Kline
  4. Center for Human Genetics, Catholic University Leuven, Leuven, Belgium

    • Jeroen Breckpot
    •  & Koenraad Devriendt
  5. Department of Pediatrics, Section of Genetics, University of Oklahoma Health Science Center, Oklahoma City, OK, USA

    • Klaas Wierenga
    •  & Elizabeth Fanning
  6. Department of Pediatrics, Division of Genetics and Genomic Medicine, Washington University School of Medicine, St. Louis, MO, USA

    • Dorothy K. Grange
  7. Department of Genetics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada

    • Gail E. Graham
  8. Division of Genetics, Department of Pediatrics, UC San Diego School of Medicine, Rady Children’s Hospital, San Diego, CA, USA

    • Carolina Galarreta
    •  & Marilyn C. Jones
  9. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

    • Usha Kini
    •  & Helen Stewart

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  1. Care for Rare Canada Consortium

    Conflict of interest

    The authors declare that they have no conflict of interest.

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    Correspondence to P. Y. Billie Au.

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    DOI

    https://doi.org/10.1038/s41431-018-0187-2