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.
Highlights
Heterozygous variants in transcription factor p63 encoded by TP63 [MIM 603273] have been linked to several autosomal dominantly inherited malformation syndromes including ankyloblepharonectodermal defects-cleft lip/palate syndrome (AEC [MIM 106260]), acro-dermo-ungual-lacrimal-tooth syndrome (ADULT [MIM 103285]), ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3 [MIM 604292]), limb-mammary syndrome (LMS [MIM 603543]), split-hand/foot malformation type 4 (SHFM4 [MIM 605289]) and isolated orofacial cleft 8 (OFC8 [MIM 618149]) [1]
TP63-related disorders have 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 [1, 2]
CLINICAL REPORT We describe six patients with cleft tongue (HP:0000221) who were referred to our Institute of Human Genetics for clinical and diagnostic evaluation
Summary
Heterozygous variants in transcription factor p63 encoded by TP63 [MIM 603273] have been linked to several autosomal dominantly inherited malformation syndromes including ankyloblepharonectodermal defects-cleft lip/palate syndrome (AEC [MIM 106260]), acro-dermo-ungual-lacrimal-tooth syndrome (ADULT [MIM 103285]), ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3 [MIM 604292]), limb-mammary syndrome (LMS [MIM 603543]), split-hand/foot malformation type 4 (SHFM4 [MIM 605289]) and isolated orofacial cleft 8 (OFC8 [MIM 618149]) [1]. The variant, c.3G>T, affects the first transcription start site of p63 and is predicted to lead to impaired function of the TAp63 isoforms. He showed the following facial features: narrow face (HP:0000275), reddish hair (HP:0002297), freckles (HP:0001480), and a median furrowed tongue/cleft tongue (HP:0000221).
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