Romano Ferruccio, Cerminara Maria, De Marco Patrizia, Iacomino Michele, Di Duca Marco, Tortora Domenico, Pavanello Marco, Piatelli Gianluca, Scala Marcello, Zara Federico, Puliti Aldamaria, Capra Valeria
Genomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Birth Defects Res. 2025 Feb;117(2):e2446. doi: 10.1002/bdr2.2446.
Chiari malformation type 1 (CMI) is defined by the herniation of cerebellar tonsils of 5 mm or more, with possible neurological consequences, including compression of the neural tissue and/or anomalies in cerebral spinal fluid circulation. The etiology of CMI is not fully elucidated, with both genetic and environmental factors being involved. Several genes and pathways involved in bone development are pointed out like genes of the WNT, FGF, and BMP signaling pathways. More recently, the crucial role played by chromatin remodeling genes in the pathogenesis of CMI has increasingly emerged.
In this paper, we discuss a familial case of CMI and a single patient, harboring variants in chromatin remodeling genes, identified by whole exome sequencing.
The first is a family with three affected members and one sibling with a cerebellar tonsil herniation of < 5 mm. The three CMI patients harbor a heterozygous missense variant in the SETD2 gene, whose truncating variants are responsible for Luscan-Lumish syndrome. A second variant in HP1BP3, a gene not previously associated with human pathology, with evidence of skeletal anomalies in mice models, was found in the three patients and also in the girl with a herniation of < 5 mm. The second case is a proband with a de novo variant in KMT2A, associated with Wiedemann-Steiner syndrome, in which anomalies of the craniocervical junction are described.
We highlight the importance of chromatin remodeling genes in both isolated and syndromic CMI and suggest the potential role of HP1BP3 as a possible modifier gene in CMI pathogenesis, even if this association needs to be further clarified.
1型Chiari畸形（CMI）定义为小脑扁桃体疝出5毫米或以上，可能导致神经学后果，包括神经组织受压和/或脑脊液循环异常。CMI的病因尚未完全阐明，涉及遗传和环境因素。有人指出，一些参与骨骼发育的基因和信号通路，如WNT、FGF和BMP信号通路的基因。最近，染色质重塑基因在CMI发病机制中所起的关键作用日益显现。
在本文中，我们讨论了一例CMI家族病例和一名通过全外显子组测序鉴定出携带染色质重塑基因突变的患者。
第一例是一个有三名患病成员的家族，还有一名小脑扁桃体疝出<5毫米的同胞。三名CMI患者在SETD2基因中存在杂合错义变异，该基因的截短变异会导致Luscan-Lumish综合征。在三名患者以及小脑扁桃体疝出<5毫米的女孩中，发现了HP1BP3基因中的第二个变异，该基因以前未与人类病理学相关联，但在小鼠模型中有骨骼异常的证据。第二例是一名先证者，其KMT2A基因存在新发变异，与维德曼-施泰纳综合征相关，该综合征中描述了颅颈交界处的异常。
我们强调了染色质重塑基因在孤立性和综合征性CMI中的重要性，并提出HP1BP3作为CMI发病机制中可能的修饰基因的潜在作用，尽管这种关联需要进一步阐明。
