Supplementary Material for: Expanding the Clinical Spectrum of RERE-Related Disorders: A Case report of Neurodevelopmental Disorder with Brain Malformations Including Chiari Type I

Abstract
Introduction: Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH) is a rare genetic condition caused by heterozygous pathogenic variants in the RERE gene, which encodes a transcriptional co-repressor essential for embryonic development. Most reported cases result from de novo variants and show a broad spectrum of neurodevelopmental and structural abnormalities. This report expands the phenotypic spectrum of NEDBEH by describing the first association with a Chiari type I malformation.
Case presentation: We report a 26-year-old Colombian male presenting with global developmental delay, progressive spasticity, mild dysmorphic features and a Chiari type I malformation, a finding not previously linked to RERE variants. Whole-exome sequencing identified a heterozygous de novo missense variant in RERE (NM_001042681.3:c.815A>G; p.Tyr272Cys), initially classified as a variant of uncertain significance but supported as likely pathogenic according to ACMG criteria (PP3, PM2). The RERE gene functions as a retinoic acid–dependent transcriptional cofactor, a pathway critical for hindbrain segmentation and morphogenesis, providing a plausible mechanism for the cerebellar anomaly observed.
Conclusion: This case broadens the clinical spectrum of RERE-related NEDBEH, suggesting potential cerebellar involvement secondary to disrupted retinoic acid signaling. It emphasizes the importance of genomic testing for patients with neurodevelopmental delay and structural brain malformations, enabling accurate diagnosis, genetic counseling, and deeper understanding of rare developmental disorders.

摘要
引言：伴或不伴脑、眼或心脏异常的神经发育障碍（Neurodevelopmental disorder with or without anomalies of the brain, eye, or heart, NEDBEH）是一种罕见遗传病，由RERE基因的杂合致病性变异所致，该基因编码胚胎发育所必需的转录共抑制因子。目前报道的多数病例由新发变异引起，临床表现为广泛的神经发育与结构异常。本研究通过首次报道该疾病与I型小脑扁桃体下疝畸形（Chiari type I malformation）的关联，拓展了NEDBEH的表型谱。

病例报告：我们报道1例26岁哥伦比亚男性患者，表现为全面发育迟缓、进行性痉挛状态、轻度畸形特征，以及此前未与RERE变异相关联的I型小脑扁桃体下疝畸形。全外显子测序（Whole-exome sequencing）检测到RERE基因上存在一处杂合新发错义变异（NM_001042681.3:c.815A>G; p.Tyr272Cys），该变异最初被归类为意义未明变异，但依据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics, ACMG）标准（PP3、PM2）被判定为可能致病性变异。RERE基因作为视黄酸依赖性转录辅因子发挥功能，该通路对后脑分段与形态发生至关重要，可为本次观察到的小脑异常提供合理的发病机制解释。

结论：本病例拓宽了RERE相关NEDBEH的临床表型谱，提示视黄酸信号通路受损可能继发小脑受累。本研究强调了对伴有神经发育迟缓和脑结构畸形的患者开展基因组检测的重要性，可助力实现精准诊断、遗传咨询，并加深对罕见发育障碍的认知。