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Neurogenetics. 2019 May;20(2):91-98. doi: 10.1007/s10048-019-00577-2. Epub 2019 Apr 13.

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

Author information

1
Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, 20037, DC, USA.
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, Paris, France.
6
Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.
7
Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
8
Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, 02115, MA, USA.
9
Division of Pediatric Neurology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
10
Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, 20037, DC, USA. chiara.manzini@gmail.com.

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.

KEYWORDS:

Hydrocephalus; Joubert syndrome; Lissencephaly; Polymicrogyria

PMID:
30982090
DOI:
10.1007/s10048-019-00577-2

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