Institute of Human Genetics, University Medical Center Göttingen, Göttingen, Germany.
Department of Pediatric Neurology, Klinikum Kassel, Kassel, Germany.
Eur J Hum Genet. 2022 Feb;30(2):211-218. doi: 10.1038/s41431-021-00967-x. Epub 2021 Oct 11.
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.
转录因子 p63 的变异与几种常染色体显性遗传的畸形综合征有关。这些疾病具有重叠的表型特征，以下特征的各种组合：外胚层发育不良、分裂手/足畸形/并指、泪管阻塞、乳房和/或乳头发育不良、丝状粘连的永久性粘连、尿道下裂和唇裂/腭裂。我们描述了一个有六名个体的家族，他们表现出一种引人注目的新型表型，其特征是舌裂或沟状、脸窄、红头发、雀斑和各种足部畸形。全外显子组测序（WES）鉴定了一个影响翻译起始密码子（p.1Met？）的新型杂合变异 c.3G>T 。Sanger 测序证实了这一独特变异在所有六个受影响的家族成员中的显性遗传。总之，我们的发现表明，影响第一个翻译起始密码子的 TP63 杂合变异导致一种新型表型，以舌裂为主要特征，扩大了与 TP63 相关疾病的复杂基因型和表型谱。
