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Metabotropic glutamate receptor 7 (mGluR7), encoded by <jats:italic>GRM7,<\/jats:italic> is a presynaptic G\u2010protein\u2010coupled glutamate receptor critical for synaptic transmission. We previously proposed <jats:italic>GRM7<\/jats:italic> 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 <jats:italic>GRM7<\/jats:italic> biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Exome sequencing and family\u2010based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with <jats:italic>GRM7<\/jats:italic> biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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&gt;A:p.Glu891Lys and c.1973G&gt;A:p.Arg685Gln) and one homozygous stop\u2010gain variant (c.1975C&gt;T:p.Arg659Ter). Developmental delay, neonatal\u2010 or infantile\u2010onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic\u2013pituitary\u2013axis 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\u00a0years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic <jats:italic>GRM7<\/jats:italic> pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.51003","type":"journal-article","created":{"date-parts":[[2020,4,14]],"date-time":"2020-04-14T10:40:33Z","timestamp":1586860833000},"page":"610-627","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Biallelic <i>GRM7<\/i> variants cause epilepsy, microcephaly, and cerebral atrophy"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2233-3423","authenticated-orcid":false,"given":"Dana","family":"Marafi","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics Baylor College of Medicine Houston Texas 77030"},{"name":"Department of Pediatrics Faculty of Medicine Kuwait University P.O. 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