Familial cleft tongue caused by a unique translation initiation codon variant in TP63

Abstract

Variants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.

Fig. 1. Overview of the identified translation initiation codon variant in TP63 on genomic and protein level.

A Chromatograms of the identified TP63 variant in six affected family members (I.2, II.1, II.3, III.1, III.3 and III.4: c.3G>T; p.Met1?). B Schematic diagram of the human TP63 gene structure. Alternative promoter use produces TA (transactivation) and N-terminally truncated (ΔN) isoforms, and alternative splicing produces C-terminal variants (α, β, γ). Colors within exons correspond to the different functional domains. Red arrow indicates the TP63 variant identified within this study. Orange arrow indicates the most likely alternatively used start codon at position 40, resulting in a shortened version of the TAp63 isoforms. Different TP63-associated disorders (ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC); acro-dermo-ungual-lacrimal-tooth syndrome (ADULT); ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3); limb-mammary syndrome (LMS); split-hand/foot malformation type 4 (SHFM4)) and the typical location of their variant are indicated by black brackets. C Comparison of the six major isoforms encoded by TP63. Isoforms in the red box are potentially affected by the TP63 variant p.Met1?. Colors correspond to the different functional domains.

Fig. 2. Pedigree and clinical characteristics of individuals carrying the heterozygous c.3G>A variant in TP63.

A Family pedigree, unfilled shapes denote healthy individuals, filled shapes indicate those family members who are clinically affected. B Clinical characteristics of patient II.1, II.3, III.1, III.3 and III.4. Facial features included a long narrow face (HP:0000275), hypotrophic jaw muscles (HP:0045037), reddish hair (HP:0002297), freckels (HP:0001480) and a midline furrow of the tongue (HP:0000221).