EPCO-56. RARE COMBINATION OF PEDIATRIC POSTERIOR FOSSA EPENDYMOMA GROUP A, CONSTITUTIONAL KMT2D ALA2497VAL VARIANT AND CONGENITAL SOLITARY KIDNEY

Abstract Ependymoma in children is rarely associated with pathogenic germline variants. We describe co-occurrence of posterior fossa group A ependymoma, constitutional KMT2D (MLL2) variant of unknown clinical significance (VUS), and congenital solitary kidney in a child. KMT2D encodes a histone methyltransferase. Its constitutional loss-of-function variants are associated with Kabuki syndrome Type 1. A healthy 3-year-old identical twin boy presented with headache, ataxia, dysphagia and dysarthria. Brain MRI revealed calcified right-sided posterior fossa mass. Spine MRI showed solitary right kidney. His identical twin also had solitary right kidney. Tumor was partially resected. Pathology showed posterior fossa group A ependymoma with loss of H3K27me3 trimethylation and EZHIP expression. OncoKids somatic panel showed VUSs in KMT2D (NM_003482.3: c.7490C>T, p.Ala2497Val) and CHD7 (NM_017780:c.2830C>T, p.Arg944Cys) at variant allele frequencies of 49%. Targeted Sanger sequencing of blood demonstrated that the KMT2D variant was of germline origin. Germline testing for the CHD7 variant was not performed, but also presumed germline. Patient did not have overt features suggestive of Kabuki or CHARGE syndromes. KMT2D is implicated in neural crest cell development and migration. Loss of function variants in KMT2D are associated with autosomal dominant Kabuki syndrome affecting multiple systems including renal and cerebellar anomalies. To date, KMT2D Ala2497Val has not been linked to Kabuki syndrome. Case reports have associated various cancers with Kabuki syndrome, including one report of a spinal ependymoma, suggesting a cancer predisposition. CHD7 is also required for renal and cerebellar development. Germline variants of CHD7 are associated with CHARGE syndrome. The KMT2D and CHD7 variants are not predicted to reach pathogenic classification on their own. However, variants in both genes may contribute to cancer and syndromic disorders with renal and cerebellar anomalies. We posit that the combination of both variants contributed to this patient’s ependymoma and congenital solitary kidney. Additional studies are required to confirm this.