PDF(Pubmed)
Abstract：
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.
摘要：
已经在先前发表的七个在CAPN15基因中具有双等位基因致病变体的个体中描述了肠神经发育综合征。据报道，双等位基因错义变体表现为眼部异常和发育迟缓的表型，而功能变异的双等位基因丧失表现出包括小头畸形和颅面畸形的表型，心脏和泌尿生殖系统畸形,和异常的神经系统活动。我们报告了来自三个不相关家庭的六个人，这些人在CAPN15中具有双等位基因有害变体，其表型与先前针对该疾病描述的表型重叠。在受影响的个人中，四个人展示了Dandy-Walker畸形的经典三合会的影像学证据，包括发育不全的疣，第四脑室扩大,和环形高程。先前尚未报道小脑异常与CAPN15相关疾病有关。这里,我们提供了三个不相关的家庭，其发现与眼胃肠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。我们的发现为文献添加了六个分子确认的病例，并另外建立了Dandy-Walker畸形与双等位基因CAPN15变体的新关联，从而扩大了受CAPN15相关疾病影响的患者的神经系统。
