Syndromic Hirschsprung Disease With a Novel De Novo Sense Exonic SVA Insertion of TCF20.

Abstract

Transcription Co-Activator Factor 20 (TCF20) Associated Neurodevelopmental Disorder (TAND, OMIM: 618430) is a rare autosomal dominant neurodevelopmental disorder most commonly associated with disruptive TCF20 variants and features overlapping Smith-Magenis syndrome (SMS, OMIM: 182290). Here we present a 40-year-old man with Hirschsprung disease (HD), intellectual disability, coarse facial features, sleep disturbances, and recurrent infections in whom whole-exome sequencing revealed a de novo heterozygous SVA retrotransposon insertion at c.1920_1921 in Exon 2 of TCF20 (OMIM: 603107), predicted to disrupt the primary TCF20 transcript (NM_005650.4), consistent with a molecular diagnosis of TAND. This SVA insertion has not been previously reported. The occurrence of congenital, biopsy-confirmed Hirschsprung disease in this patient suggests that intestinal aganglionosis may represent an uncommon extension of the gastrointestinal phenotype associated with TAND, in which chronic constipation and gastrointestinal dysmotility are already recognized. This case also underscores the phenotypic and molecular heterogeneity associated with mobile transposable elements of the human exome, alongside the clinical importance of transposon analysis.