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Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556

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Abstract

Genetic mutations associated with brain malformations can lead to a spectrum of severity and it is often difficult to determine whether there are additional pathogenic variants contributing to the phenotype. Here, we present a family affected by a severe brain malformation including bilateral polymicrogyria, hydrocephalus, patchy white matter signal changes, and cerebellar and pontine hypoplasia with elongated cerebellar peduncles leading to the molar tooth sign. While the malformation is reminiscent of bilateral frontoparietal polymicrogyria (BFPP), the phenotype is more severe than previously reported and also includes features of Joubert syndrome (JBTS). Via exome sequencing, we identified homozygous truncating mutations in both ADGRG1/GPR56 and KIAA0556, which are known to cause BFPP and mild brain-specific JBTS, respectively. This study shows how two independent mutations can interact leading to complex brain malformations.

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Acknowledgements

The authors would like to thank the family for participating in our studies. Adam Wong at the GWU high-performance computing cluster Colonial One and Dr. Annapurna Poduri at Boston Children’s Hospital for initial input on the brain imaging.

Funding

This research was funded by a March of Dimes Research Grant to M.C.M. M.A.S and was supported by the Deanship of Scientific Research, King Saud University, Riyadh, Saudi Arabia, via research group project number RGP-VPP-301.

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Author notes

  1. Edmund S. Cauley and Ahlam Hamed contributed equally to this work.

Authors and Affiliations

  1. Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, 20037, DC, USA

    Edmund S. Cauley, Samantha Martinez & M. Chiara Manzini

  2. Department of Pediatrics and Child Health, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

    Ahlam Hamed, Inaam N. Mohamed & Maha Elseed

  3. Department of Biochemistry, Faculty of Medicine, University of Khartoum, Khartoum, Sudan

    Ashraf Yahia, Fatima Abozar & Liena Elsayed

  4. Department of Biochemistry, Faculty of Medicine, National University, Khartoum, Sudan

    Ashraf Yahia

  5. Institut du Cerveau et de la Moelle épinière, INSERM U1127, CNRS UMR7225, Sorbonne Universités UMR_S1127, Paris, France

    Ashraf Yahia

  6. Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan

    Rayan Abubakr

  7. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

    Mahmoud Koko

  8. Division of Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, 02115, MA, USA

    Xianhua Piao

  9. Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Mustafa A. Salih

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  1. Edmund S. Cauley
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Cauley, E.S., Hamed, A., Mohamed, I.N. et al. Overlap of polymicrogyria, hydrocephalus, and Joubert syndrome in a family with novel truncating mutations in ADGRG1/GPR56 and KIAA0556. Neurogenetics 20, 91–98 (2019). https://doi.org/10.1007/s10048-019-00577-2

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