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 four seemingly distinct phenotypes including frontotemporal lissencephaly, epilepsy, autism and probably schizophrenia. Notably, we observed a significantly higher proportion of loss-of-function variants in the biallelic compared to the monoallelic cohort, where the variant spectrum included missense and splice-site variants. We assessed the impact of two canonical splice-site variants observed as biallelic or monoallelic variants in individuals with moderately affected or normal cerebellum and demonstrated exon skipping causing in-frame loss of 46 or 52 amino acids in the central RELN domain. Previously reported functional studies demonstrated severe reduction in overall RELN secretion caused by heterozygous missense variants p.Cys539Arg and p.Arg3207Cys associated with lissencephaly suggesting a dominant-negative effect. We conclude that biallelic variants resulting in complete absence of RELN expression are associated with a consistent and severe phenotype that includes cerebellar hypoplasia. However, reduced expression of RELN remains sufficient to maintain nearly normal cerebellar structure. Monoallelic variants are associated with incomplete penetrance and variable expressivity even within the same family and may have dominant-negative effects. Reduced RELN secretion in heterozygous individuals affects only cortical structure whereas the cerebellum remains intact. Our data expand the spectrum of RELN-related neurodevelopmental disorders ranging from lethal brain malformations to adult phenotypes with normal brain imaging.

中文翻译：

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RELN 的单等位基因和双等位基因突变是一系列分级神经发育障碍的基础。


Reelin 是一种大型细胞外蛋白，在大脑发育和功能中发挥着多种关键作用。它由 RELN 编码，RELN 最初被鉴定为在 reeler 小鼠中被破坏的基因，reeler 小鼠是一种典型的神经突变体，表现出共济失调、震颤和“旋转”步态。在人类中，RELN 的双等位基因变异与伴有小脑发育不全的隐性无脑畸形变异相关，该变异与具有异常皮质结构、小海马和严重小脑发育不全的纯合小鼠突变体非常匹配。尽管该基因很大，但之前仅报道了来自 6 个家族的 11 名患有 RELN 相关无脑畸形伴小脑发育不全的个体。尽管推定的功能丧失变异在人群中实际上不存在（功能丧失不耐受的概率 = 1），但这些家族中的杂合子携带者被简要报告为未受影响。在这里，我们提供了来自 4 个具有双等位基因家族的 7 名个体的数据，以及来自 7 个具有 RELN 单等位基因（杂合）变异和额颞叶或颞侧为主的无脑畸形变异的家族的 13 名个体的数据。一些具有单等位基因变异的个体患有中度额颞叶无脑畸形，但小脑结构正常、智力障碍和严重的行为功能障碍。然而，一名成年人的 MRI 异常，但智力和神经系统特征正常。全面的文献分析支持单等位基因 RELN 变异在四种看似不同的表型中的因果作用，包括额颞叶无脑畸形、癫痫、自闭症和可能的精神分裂症。 值得注意的是，与单等位基因组相比，我们观察到双等位基因中功能丧失变异的比例明显更高，其中变异谱包括错义和剪接位点变异。我们评估了在中度受影响或正常小脑个体中作为双等位基因或单等位基因变异观察到的两个典型剪接位点变异的影响，并证明外显子跳跃导致中央 RELN 结构域中 46 或 52 个氨基酸的框内丢失。先前报道的功能研究表明，与无脑畸形相关的杂合错义变异 p.Cys539Arg 和 p.Arg3207Cys 导致总体 RELN 分泌严重减少，表明存在显性负效应。我们得出的结论是，导致 RELN 表达完全缺失的双等位基因变异与包括小脑发育不全在内的一致且严重的表型相关。然而，RELN 表达的减少仍然足以维持几乎正常的小脑结构。单等位基因变异与不完全外显率和可变表达性相关，即使在同一家族内也是如此，并且可能具有显性负效应。杂合子个体中 RELN 分泌减少仅影响皮质结构，而小脑保持完整。我们的数据扩大了 RELN 相关神经发育障碍的范围，从致命的脑畸形到具有正常脑成像的成人表型。