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251 Expanding the genetic and clinical spectrum of the nono-associated x-linked intellectual disability syndrome with left ventricular non-compaction

Purpose of study A two-year-old boy presented to the University of Utah’s Penelope Undiagnosed Disease Program with global developmental delay, congenital heart disease consisting of dilated cardiomyopathy with left ventricular non-compaction and Ebstein’s anomaly, strabismus, undescended testes, and mixed sleep apnea. He was small (length and weight <1%) with preserved head size (85%). On exam, we noted a triangular shape of the face with wide-spaced eyes, downslanting palpebral fissures, and a thin vermillion of the upper lip. Brain MRI showed a thick corpus callosum and a mild Chiari I malformation. Methods used Exome sequencing was performed, as well as follow-up RNA studies and family segregation analysis, to aid in diagnosis. Summary of results Exome sequencing identified a maternally-inherited small intronic deletion in the NONO gene. This X-linked gene encodes a nuclear protein involved in RNA metabolism. Loss-of-function variants have been associated with a syndromic form of intellectual disability (Mircsof et al. 2015) and with non-compaction cardiomyopathy (Reinstein et al. 2016, Scott et al. 2017). Notwithstanding the clinical overlap with the few reported cases, without functional studies this intronic NONO deletion was initially classified as a variant of uncertain significance. However, follow up splicing studies demonstrated intron readthrough and the use of an alternative donor 13 bases into the intron, causing a frameshift and creating a transcript susceptible to nonsense-mediated decay. Also, family segregation studies showed that the variant occurred de novo in the boy’s unaffected mother. Conclusions Based on these findings this novel NONO variant was reclassified as pathogenic. This eighth known case expands and further delineates the neurological and cardiac phenotypes of this rare X-linked condition.