Monoallelic and biallelic mutations in RELN underlie a graded series of neurodevelopmental disorders

作者：Nataliya Di Donato, Renzo Guerrini, Charles J. Billington, A. James Barkovich, Philine Dinkel, Elena Freri, Michael Heide, Elliot S. Gershon, Tracy S. Gertler, Robert J. Hopkin, Suma Jacob, Sarah Keedy, Daniz Kooshavar, Paul J. Lockhart, Dietmar Lohmann, Iman G. Mahmoud, Elena Parrini, Evelin Schröck, Giulia Severi, Andrew E. Timms, Richard Webster, Mary Willis, Maha S. Zaki, Joseph G. Gleeson, Richard J. Leventer, William B. Dobyns · 发表于：Brain · 年份：2022 · DOI：10.1093/brain/awac164 · 被引用次数：23 · 研究领域：Fetal and Pediatric Neurological Disorders、RNA Research and Splicing、RNA modifications and cancer

Reelin, a large extracellular protein, plays several critical roles in brain development and function. It is encoded by RELN, first identified as the gene disrupted in the reeler mouse, a classic neurological mutant exhibiting ataxia, tremors and a 'reeling' gait. In humans, biallelic variants in RELN have been associated with a recessive lissencephaly variant with cerebellar hypoplasia, which matches well with the homozygous mouse mutant that has abnormal cortical structure, small hippocampi and severe cerebellar hypoplasia. Despite the large size of the gene, only 11 individuals with RELN-related lissencephaly with cerebellar hypoplasia from six families have previously been reported. Heterozygous carriers in these families were briefly reported as unaffected, although putative loss-of-function variants are practically absent in the population (probability of loss of function intolerance = 1). Here we present data on seven individuals from four families with biallelic and 13 individuals from seven families with monoallelic (heterozygous) variants of RELN and frontotemporal or temporal-predominant lissencephaly variant. Some individuals with monoallelic variants have moderate frontotemporal lissencephaly, but with normal cerebellar structure and intellectual disability with severe behavioural dysfunction. However, one adult had abnormal MRI with normal intelligence and neurological profile. Thorough literature analysis supports a causal role for monoallelic RELN variants in ...