De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth

Abstract

Recently, germline variants of the transcriptional co-regulator gene TCF20 have been implicated in the aetiology of autism spectrum disorders (ASD). However, the knowledge about the associated clinical picture remains fragmentary. In this study, two individuals with de novo TCF20 sequence variants were identified in a cohort of 313 individuals with intellectual disability of unknown aetiology, which was analysed by whole exome sequencing using a child-parent trio design. Both detected variants - one nonsense and one frameshift variant - were truncating. A comprehensive clinical characterisation of the patients yielded mild intellectual disability, postnatal tall stature and macrocephaly, obesity and muscular hypotonia as common clinical signs while ASD was only present in one proband. The present report begins to establish the clinical picture of individuals with de novo nonsense and frameshift variants of TCF20 which includes features such as proportionate overgrowth and muscular hypotonia. Furthermore, intellectual disability/developmental delay seems to be fully penetrant amongst known individuals with de novo nonsense and frameshift variants of TCF20, whereas ASD is shown to be incompletely penetrant. The transcriptional co-regulator gene TCF20 is hereby added to the growing number of genes implicated in the aetiology of both ASD and intellectual disability. Furthermore, such de novo variants of TCF20 may represent a novel differential diagnosis in the overgrowth syndrome spectrum.

Figure 1

(a–f) Facial phenotypes of the two individuals with de novo nonsense and frameshift variants of TCF20: Facial images of Individual 1 at the age of 7 years (a, b) and Individual 2 at the age of 7 (c, d) and 12 years (e, f). No major facial dysmorphism is apparent.

Figure 2

Graphical view of protein TCF20 with the variants c.955C>T (p.(Gln319*)) and c.3837del (p.(Asp1280Ilefs*71)) identified in individuals 1 and 2: the variants c.1534 A>G (p.(Lys512Glu)) and c.3518delA (p.(Lys1173Argfs*5)) identified by Babbs et al are highlighted. The previously annotated PEST domains (P1-P3), the nuclear localisation signal domains (N1-N3) and the zinc finger domain (ZF) are shown. Scale bar corresponds to 100 amino acids (AA).