Novel association of Dandy-Walker malformation with CAPN15 variants expands the phenotype of oculogastrointestinal neurodevelopmental syndrome

• Published in: American journal of medical genetics. Part A Vol. 191; no. 11; pp. 2757 - 2767
• Main Authors: Beaman, M Makenzie, Guidugli, Lucia, Hammer, Monia, Barrows, Chelsea, Gregor, Anne, Lee, Sangmoon, Deak, Kristen L, McDonald, Marie T, Jensen, Courtney, Zaki, Maha S, Masri, Amira T, Hobbs, Charlotte A, Gleeson, Joseph G, Cohen, Jennifer L
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.11.2023
• Subjects: Animals; Calpain - genetics; Cerebellar Vermis; Cerebellum; Cerebellum - abnormalities; Dandy-Walker Syndrome - diagnosis; Dandy-Walker Syndrome - genetics; Humans; Mice; Microcephaly - complications; Microencephaly; Neurodevelopmental disorders; Phenotype; Phenotypes; Ventricle; Ventricles (cerebral); Dandy-Walker malformation; calpain; cerebellar dysgenesis; Purkinje cells; phenotype expansion; oculogastrointestinal neurodevelopmental syndrome
• ISSN: 1552-4825; 1552-4833; 1552-4833
• DOI: 10.1002/ajmg.a.63363

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.