Overlap of polymicrogyria, hydrocephalus, and Joubert Syndrome

Overlap of polymicrogyria, hydrocephalus, and Joubert Syndrome

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

Edmund S. Cauley MPhil1,10, Ahlam Hamed MD2,10, Inaam N. Mohammed MD2, Maha Elseed MD2, Samantha Martinez1, Ashraf Yahia MSc3,4,5, Fatima Abuzar3, Rayan Abubakr MSc6, Mahmoud Koko MSc7, Liena Elsayed PhD3, Xianhua Piao MD8, Mustafa A. Salih MD9, M. Chiara Manzini PhD1*

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

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

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

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

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

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

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

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

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

10 these authors contributed equally to the study

 

Abstract (126 words)

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 malfromation including bilateral polymicrogyria, hydrocephalus, white matter defects, 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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