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

  • Edmund S. Cauley
  • Ahlam Hamed
  • Inaam N. Mohamed
  • Maha Elseed
  • Samantha Martinez
  • Ashraf Yahia
  • Fatima Abozar
  • Rayan Abubakr
  • Mahmoud Koko
  • Liena Elsayed
  • Xianhua Piao
  • Mustafa A. Salih
  • M. Chiara ManziniEmail author
Original Article


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.


Polymicrogyria Hydrocephalus Joubert syndrome Lissencephaly 



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 information

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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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Edmund S. Cauley
    • 1
  • Ahlam Hamed
    • 2
  • Inaam N. Mohamed
    • 2
  • Maha Elseed
    • 2
  • Samantha Martinez
    • 1
  • Ashraf Yahia
    • 3
    • 4
    • 5
  • Fatima Abozar
    • 3
  • Rayan Abubakr
    • 6
  • Mahmoud Koko
    • 7
  • Liena Elsayed
    • 3
  • Xianhua Piao
    • 8
  • Mustafa A. Salih
    • 9
  • M. Chiara Manzini
    • 1
    Email author
  1. 1.Institute for Neuroscience, Department of Pharmacology and PhysiologyThe George Washington University School of Medicine and Health SciencesWashingtonUSA
  2. 2.Department of Pediatrics and Child Health, Faculty of MedicineUniversity of KhartoumKhartoumSudan
  3. 3.Department of Biochemistry, Faculty of MedicineUniversity of KhartoumKhartoumSudan
  4. 4.Department of Biochemistry, Faculty of MedicineNational UniversityKhartoumSudan
  5. 5.Institut du Cerveau et de la Moelle épinièreINSERM U1127, CNRS UMR7225, Sorbonne Universités UMR_S1127ParisFrance
  6. 6.Institute of Endemic DiseasesUniversity of KhartoumKhartoumSudan
  7. 7.Department of Neurology and Epileptology, Hertie Institute for Clinical Brain ResearchUniversity of TübingenTübingenGermany
  8. 8.Division of Newborn Medicine, Department of Pediatrics, Boston Children’s HospitalHarvard Medical SchoolBostonUSA
  9. 9.Division of Pediatric Neurology, College of MedicineKing Saud UniversityRiyadhSaudi Arabia

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