Department of Pediatrics, Division of Medical Genetics, Duke University, Durham, North Carolina, USA.
Medical Scientist Training Program, Duke University, Durham, North Carolina, USA.
Am J Med Genet A. 2023 Nov;191(11):2757-2767. doi: 10.1002/ajmg.a.63363. Epub 2023 Aug 19.
Oculogastrointestinal neurodevelopmental syndrome has been described in seven previously published individuals who harbor biallelic pathogenic variants in the CAPN15 gene. Biallelic missense variants have been reported to demonstrate a phenotype of eye abnormalities and developmental delay, while biallelic loss of function variants exhibit phenotypes including microcephaly and craniofacial abnormalities, cardiac and genitourinary malformations, and abnormal neurologic activity. We report six individuals from three unrelated families harboring biallelic deleterious variants in CAPN15 with phenotypes overlapping those previously described for this disorder. Of the individuals affected, four demonstrate radiographic evidence of the classical triad of Dandy-Walker malformation including hypoplastic vermis, fourth ventricle enlargement, and torcular elevation. Cerebellar anomalies have not been previously reported in association with CAPN15-related disease. Here, we present three unrelated families with findings consistent with oculogastrointestinal neurodevelopmental syndrome and cerebellar pathology including Dandy-Walker malformation. To corroborate these novel clinical findings, we present supporting data from the mouse model suggesting an important role for this protein in normal cerebellar development. Our findings add six molecularly confirmed cases to the literature and additionally establish a new association of Dandy-Walker malformation with biallelic CAPN15 variants, thereby expanding the neurologic spectrum among patients affected by CAPN15-related disease.
眼-胃肠道-神经发育综合征已在先前发表的七名个体中描述，这些个体均携带 CAPN15 基因的双等位致病性变异。已报道双等位错义变异表现为眼部异常和发育迟缓的表型，而双等位失活变异则表现为包括小头畸形和颅面异常、心脏和泌尿生殖系统畸形以及异常神经活动的表型。我们报告了来自三个无关家庭的六名个体，他们携带 CAPN15 的双等位有害变异，表型与该疾病先前描述的重叠。受影响的个体中，有四人显示出经典的 Dandy-Walker 畸形三联征的放射影像学证据，包括蚓部发育不良、第四脑室扩大和 Torcular 抬高。小脑异常以前没有与 CAPN15 相关疾病相关报道。在这里，我们介绍三个无关家庭的发现与眼-胃肠道-神经发育综合征和小脑病理学一致，包括 Dandy-Walker 畸形。为了证实这些新的临床发现，我们提供了来自小鼠模型的支持数据，表明该蛋白在正常小脑发育中具有重要作用。我们的发现将六个分子上确认的病例添加到文献中，并进一步确立了 Dandy-Walker 畸形与 CAPN15 双等位变异的新关联，从而扩大了受 CAPN15 相关疾病影响的患者的神经学谱。
