An interactive atlas of three-dimensional syndromic facial morphology.

Craniofacial phenotyping is critical for both syndrome delineation and diagnosis because craniofacial abnormalities occur in 30% of characterized genetic syndromes. Clinical reports, textbooks, and available software tools typically provide two-dimensional, static images and illustrations of the characteristic phenotypes of genetic syndromes. In this work, we provide an interactive web application that provides three-dimensional, dynamic visualizations for the characteristic craniofacial effects of 95 syndromes. Users can visualize syndrome facial appearance estimates quantified from data and easily compare craniofacial phenotypes of different syndromes. Our application also provides a map of morphological similarity between a target syndrome and other syndromes. Finally, users can upload 3D facial scans of individuals and compare them to our syndrome atlas estimates. In summary, we provide an interactive reference for the craniofacial phenotypes of syndromes that allows for precise, individual-specific comparisons of dysmorphology.

TBCK syndrome: a rare multi-organ neurodegenerative disease.

TBCK syndrome is an autosomal recessive disorder primarily characterized by global developmental delay, hypotonia, abnormal magnetic resonance imaging (MRI), and distinctive craniofacial phenotypes. High variability is observed among affected individuals and their corresponding variants, making clinical diagnosis challenging. Here, we discuss recent breakthroughs in clinical considerations, TBCK function, and therapeutic development.

Na+ and K+ transport and maturation stage ameloblast modulation.

Introduction: Enamel mineralization requires calcium transport into the extracellular matrix for the synthesis of hydroxyapatite (HA) crystals. Formation of HA releases protons into the matrix, which are then neutralized when ameloblasts modulate from cells with apical invaginations, the so-called ruffle-ended ameloblasts (RE), to smooth-ended ameloblasts (SE). Ameloblast modulation is associated with the translocation of the calcium exchanger Nckx4 to the apical border of RE, to remove Na+ from the enamel matrix in exchange for Ca2+ and K+. As enamel matures, Na+ and K+ in the matrix progressively decrease. However, the transporter to remove K+ from mineralizing enamel has not been identified. Methods: Expression of K+ exchangers and channels in secretory and maturation stage of enamel organs were compared following an RNA-seq analysis. Kcnj15, which encodes the Kir4.2 inwardly rectifying K+ channel, was found to be the most upregulated internalizing K+ transporter in maturation stage of enamel organs. Kir4.2 was immunolocalized in wt, Nckx4-/-, Wdr72-/-, and fluorosed ameloblasts. Regulation of Wdr72 expression by pH was characterized in vitro and in vivo. Results: Kir4.2 immunolocalized to the apical border of wild type (wt) mouse RE and cytosol of SE, a spatial distribution pattern shared by NCKX4. In Nckx4-/- ameloblasts, Kir4.2 also localized to the apical surface of RE and cytosol of SE. However, in fluorosed and Wdr72-/- ameloblasts, in which vesicle trafficking is disrupted, Kir4.2 remained in the cytosol. In vitro, Wdr72 was upregulated in LS8 cells cultured in medium with a pH 6.2, which is the pH of the enamel matrix underlying RE, as compared to pH 7.2 under SE. Conclusion: Taken together these results suggest that Kir4.2 participates in K+ uptake by maturation ameloblasts, and that K+ and Na+ uptake by Kir4.2 and Nckx4, respectively, may be regulated by pH through WDR72-mediated endocytosis and membrane trafficking.

Refining nosology by modelling variation among facial phenotypes: the RASopathies.

BACKGROUND: In clinical genetics, establishing an accurate nosology requires analysis of variations in both aetiology and the resulting phenotypes. At the phenotypic level, recognising typical facial gestalts has long supported clinical and molecular diagnosis; however, the objective analysis of facial phenotypic variation remains underdeveloped. In this work, we propose exploratory strategies for assessing facial phenotypic variation within and among clinical and molecular disease entities and deploy these techniques on cross-sectional samples of four RASopathies: Costello syndrome (CS), Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC) and neurofibromatosis type 1 (NF1). METHODS: From three-dimensional dense surface scans, we model the typical phenotypes of the four RASopathies as average 'facial signatures' and assess individual variation in terms of direction (what parts of the face are affected and in what ways) and severity of the facial effects. We also derive a metric of phenotypic agreement between the syndromes and a metric of differences in severity along similar phenotypes. RESULTS: CFC shows a relatively consistent facial phenotype in terms of both direction and severity that is similar to CS and NS, consistent with the known difficulty in discriminating CFC from NS based on the face. CS shows a consistent directional phenotype that varies in severity. Although NF1 is highly variable, on average, it shows a similar phenotype to CS. CONCLUSIONS: We established an approach that can be used in the future to quantify variations in facial phenotypes between and within clinical and molecular diagnoses to objectively define and support clinical nosologies.

WDR72 regulates vesicle trafficking in ameloblasts.

As the hardest tissue in the human body, tooth enamel formation is a highly regulated process involving several stages of differentiation and key regulatory genes. One such gene, tryptophan-aspartate repeat domain 72 (WDR72), has been found to cause a tooth enamel defect when deleted or mutated, resulting in a condition called amelogenesis imperfecta. Unlike the canonical genes regulating tooth development, WDR72 remains intracellularly and is not secreted to the enamel matrix space to regulate mineralization, and is found in other major organs of the body, namely the kidney, brain, liver, and heart. To date, a link between intracellular vesicle transport and enamel mineralization has been suggested, however identification of the mechanistic regulators has yet to be elucidated, in part due to the limitations associated with studying highly differentiated ameloblast cells. Here we show compelling evidence that WDR72 regulates endocytosis of proteins, both in vivo and in a novel in vitro ameloblast cell line. We elucidate WDR72's function to be independent of intracellular vesicle acidification while still leading to defective enamel matrix pH extracellularly. We identify a vesicle function associated with microtubule assembly and propose that WDR72 directs microtubule assembly necessary for membrane mobilization and subsequent vesicle transport. Understanding WDR72 function provides a mechanistic basis for determining physiologic and pathologic tissue mineralization.