2. Academic Validation
  3. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

  • Ann Clin Transl Neurol. 2020 May;7(5):610-627. doi: 10.1002/acn3.51003.
Dana Marafi 1 2,  Tadahiro Mitani 1,  Sedat Isikay 3,  Jozef Hertecant 4,  Mohammed Almannai 5,  Kandamurugu Manickam 6,  Rami Abou Jamra 7,  Ayman W El-Hattab 8,  Jaishen Rajah 9,  Jawid M Fatih 1,  Haowei Du 1,  Ender Karaca 1,  Yavuz Bayram 1,  Jaya Punetha 1,  Jill A Rosenfeld 1,  Shalini N Jhangiani 10,  Eric Boerwinkle 10 11,  Zeynep C Akdemir 1,  Serkan Erdin 12,  Jill V Hunter 13 14,  Richard A Gibbs 1 10,  Davut Pehlivan 1 13 15,  Jennifer E Posey 1,  James R Lupski 1 10 13 16
Affiliations

Affiliations

  • 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030.
  • 2 Department of Pediatrics, Faculty of Medicine, Kuwait University, P.O. Box 24923, 13110, Safat, Kuwait.
  • 3 Department of Physiotherapy and Rehabilitation, School of Health Sciences, Hasan Kalyoncu University, Gaziantep, 27000, Turkey.
  • 4 Pediatric Metabolic and Genetics Division, Tawam Hospital, Al Ain, Abu Dhabi, United Arab Emirates.
  • 5 Section of Medical Genetics, Children's Hospital, King Fahad Medical City, Riyadh, 11525, Saudi Arabia.
  • 6 Division of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, Ohio.
  • 7 Institute of Human Genetics, University Medical Center Leipzig, 04103, Leipzig, Germany.
  • 8 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates.
  • 9 Sheikh Khalifa Medical City (SKMC), P.O. Box: 51900, Abu Dhabi, United Arab Emirates.
  • 10 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, 77030.
  • 11 Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas.
  • 12 Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.
  • 13 Texas Children's Hospital, Houston, Texas, 77030.
  • 14 Department of Radiology, Baylor College of Medicine, Houston, Texas, 77030.
  • 15 Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.
  • 16 Department of Pediatrics, Baylor College of Medicine, Houston, Texas, 77030.
PMID: 32286009 DOI: 10.1002/acn3.51003
Abstract

Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.

Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.

Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic-pituitary-axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.

Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.

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