ZTTK Syndrome Expanding the Cardiac Phenotype: A Case of Shone's Complex With a Novel SON Variant and Focused Review of the Cardiac Manifestations in ZTTK Syndrome.

Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare multisystem neurodevelopmental disorder caused by heterozygous variants in SON. Presented here is a case of a four-year-old female with multiple rare manifestations including a complex neurodevelopmental disorder, Shone complex and a simple capillary malformation. Genetic analysis confirmed a novel frameshift variant in SON, which was classified as pathogenic. The patient has epilepsy and moderate-to-severe global developmental delay. Her epilepsy is well controlled with levetiracetam monotherapy. A focused literature review was undertaken and found that cardiac defects are reported in an estimated 22% of cases to date. Obstructive left-sided heart lesions are rarely reported, and this is the first reported case of Shone complex in the reported ZTTK patient cohorts. Loss-of-function variants in SON are implicated in abnormal RNA expression and splicing in genes involved in neural migration and metabolism. The literature review did not reveal an increased association between epilepsy in ZTTK patients and that in congenital heart disease compared with ZTTK patients without congenital heart disease, supporting the previous findings that SON is likely to be involved in multiple critical biological processes. Mitochondrial dysfunction was implicated in previous reports of loss-of-function SON variants and supported by the cardiac phenotype in previously reported cases.