eP081: Dandy Walker malformation in three unrelated families with biallelic variants in CAPN15 expands the phenotypic spectrum of oculogastrointestinal neurodevelopmental disorder

Oculogastrointestinal neurodevelopmental disorder (OMIM #619318) has been described in seven previously published individuals who harbor biallelic pathogenic variants the CAPN15 gene. Biallelic missense presumably lead to a more moderate phenotype of eye abnormalities and developmental delay, while loss function (nonsense, frameshift) exhibit severe phenotypes including microcephaly craniofacial abnormalities, cardiac genitourinary malformations, abnormal neurologic activity. We report six from three unrelated families harboring with overlapping those for this disorder. Of these affected, four demonstrate radiographic evidence classical triad Dandy Walker malformation hypoplastic vermis, fourth ventricle enlargement, torcular inversion. Families 1 2 have received molecular diagnoses since their were initially detail case series. Family 1: Proband was born first-cousin consanguineous parents. The proband had several dysmorphic features broad forehead, sparse eyebrows, underdeveloped ala nasi. She persistent poor weight gain along global delay hypotonia. presented congenital anomalies anal atresia single cloacal opening, labia majora, small kidneys, halluces, bilateral transverse palmar crease. MRI revealed significant vermis findings consistent malformation. A similarly deceased first cousin proband, also product union, reported intellectual disability, microcephaly, failure thrive, hypotonia, arthrogryposis, unilateral preaxial polydactyly. Chromosomal microarray non-diagnostic subsequent research exome sequencing parents homozygosity variant (NM_005632.3:c.2164delC, p.Arg716Glyfs*99); frameshift exon 8 results premature truncation transcript. 2: affected both unions. nasi, overhanging nasal tip. kidney an imperforate anus. exhibited hypotonia sensorineural deafness. showed mega cysterna magna suggestive spectrum malformations. proband’s similar microcephaly. This individual anus, urogenital fistula. deafness, no development speech. mild ventriculomegaly genome 4 (NM_005632.3:c.754dupC, p.Gln254Profs*7) that resulted 3: older sister non-consanguineous anteverted nares flattened bridge. Ocular included iridocorneal adhesions corneal clouding. stretched patent foramen ovale, large conoventricular septal defect, aortic valve severely aorta, aberrant right subclavian artery. rectovestibular fistula slightly asymmetric sacrum noted on radiograph. brain agenesis posterior fossa arachnoid cyst. No intra-abdominal visualized via ultrasound. Proband’s microphthalmos, strabismic amblyopia, monocular exotropia, coloboma. pulmonic stenosis superior vena cavae, as well kidneys. Sacral sacral dimple tethered spinal cord. Her enlarged ventricles found carry affecting CAPN15: whole-gene deletion part maternally inherited chromosome 16p13.3 (([hg19] chr16:84116-692192) paternally likely (NM_005632.3:c.2594T>C, p.Leu865Pro). In silico tools (SIFT, Polyphen2, REVEL) are prediction being deleterious. Furthermore, is absent gnomAD; Limbr, PhyloP, PhastCons algorithms predict variant’s locus strongly constrained against variation. Cerebellar not association CAPN15-related disease. Here we present display oculogastrointestinal additional cerebellar pathology To corroborate novel clinical findings, note supporting prominent protein expression Purkinje cells postnatal adult mouse suggesting important role normal development. Our add molecularly confirmed cases literature additionally establish new variants, thereby expanding associated condition.