Phenotyping: targeting genotype's rich cousin for diagnosis.

There are many current and evolving tools to assist clinicians in their daily work of phenotyping. In medicine, the term 'phenotype' is usually taken to mean some deviation from normal morphology, physiology and behaviour. It is ascertained via history, examination and investigations, and a primary aim is diagnosis. Therefore, doctors are, by necessity, expert 'phenotypers'. There is an inherent and partially realised power in phenotypic information that when harnessed can improve patient care. Furthermore, phenotyping developments are increasingly important in an era of rapid advances in genomic technology. Fortunately, there is an expanding network of phenotyping tools that are poised for clinical translation. These tools will preferentially be implemented to mirror clinical workflows and to integrate with advances in genomic and information-sharing technologies. This will synergise with and augment the clinical acumen of medical practitioners. We outline key enablers of the ascertainment, integration and interrogation of clinical phenotype by using genetic diseases, particularly rare ones, as a theme. Successes from the test bed or rare diseases will support approaches to common disease.

The facial evolution: looking backward and moving forward.

Three-dimensional (3D) facial analysis is ideal for high-resolution, nonionizing, noninvasive objective, high-throughput phenotypic, and phenomic studies. It is a natural complement to (epi)genetic technologies to facilitate advances in the understanding of rare and common diseases. The face is uniquely reflective of the primordial tissues, and there is evidence supporting the application of 3D facial analysis to the investigation of variation and disease including studies showing that the face can reflect systemic health, provides diagnostic clues to disorders, and that facial variation reflects biological pathways. In addition, facial variation has been related to evolutionary factors. The purpose of this review is to look backward to suggest that knowledge of human evolution supports, and may instruct, the application and interpretation of studies of facial morphology for documentation of human variation and investigation of its relationships with health and disease. Furthermore, in the context of advances of deep phenotyping and data integration, to look forward to suggest approaches to scalable implementation of facial analysis, and to suggest avenues for future research and clinical application of this technology.

Intersections of epigenetics, twinning and developmental asymmetries: insights into monogenic and complex diseases and a role for 3D facial analysis.

For decades the relationships of twinning and alterations in body patterning, such as laterality and asymmetry, have been investigated. However, the tools to define and quantify these relationships have been limited and the majority of these studies have relied on associations with subjectively defined phenotypes. The emerging technologies of 3-dimensional (3D) facial scanning and geometric morphometrics are providing the means to establish objective criteria, including measures of asymmetry, which can be used for phenotypic classification and investigations. Additionally, advances in molecular epigenetics provide new opportunities for novel investigations of mechanisms central to early developmental processes, twinning and related phenotypes. We review the evidence for overlapping etiologies of twinning, asymmetry and selected monogenic and complex diseases, and we suggest that the combination of epigenetic investigations with detailed and objective phenotyping, utilizing 3D facial analysis tools, can reveal insights into the genesis of these phenomena.

3-Dimensional Facial Analysis-Facing Precision Public Health.

Precision public health is a new field driven by technological advances that enable more precise descriptions and analyses of individuals and population groups, with a view to improving the overall health of populations. This promises to lead to more precise clinical and public health practices, across the continuum of prevention, screening, diagnosis, and treatment. A phenotype is the set of observable characteristics of an individual resulting from the interaction of a genotype with the environment. Precision (deep) phenotyping applies innovative technologies to exhaustively and more precisely examine the discrete components of a phenotype and goes beyond the information usually included in medical charts. This form of phenotyping is a critical component of more precise diagnostic capability and 3-dimensional facial analysis (3DFA) is a key technological enabler in this domain. In this paper, we examine the potential of 3DFA as a public health tool, by viewing it against the 10 essential public health services of the "public health wheel," developed by the US Centers for Disease Control. This provides an illustrative framework to gage current and emergent applications of genomic technologies for implementing precision public health.

Initiating an undiagnosed diseases program in the Western Australian public health system.

BACKGROUND: New approaches are required to address the needs of complex undiagnosed diseases patients. These approaches include clinical genomic diagnostic pipelines, utilizing intra- and multi-disciplinary platforms, as well as specialty-specific genomic clinics. Both are advancing diagnostic rates. However, complementary cross-disciplinary approaches are also critical to address those patients with multisystem disorders who traverse the bounds of multiple specialties and remain undiagnosed despite existing intra-specialty and genomic-focused approaches. The diagnostic possibilities of undiagnosed diseases include genetic and non-genetic conditions. The focus on genetic diseases addresses some of these disorders, however a cross-disciplinary approach is needed that also simultaneously addresses other disorder types. Herein, we describe the initiation and summary outcomes of a public health system approach for complex undiagnosed patients - the Undiagnosed Diseases Program-Western Australia (UDP-WA). RESULTS: Briefly the UDP-WA is: i) one of a complementary suite of approaches that is being delivered within health service, and with community engagement, to address the needs of those with severe undiagnosed diseases; ii) delivered within a public health system to support equitable access to health care, including for those from remote and regional areas; iii) providing diagnoses and improved patient care; iv) delivering a platform for in-service and real time genomic and phenomic education for clinicians that traverses a diverse range of specialties; v) retaining and recapturing clinical expertise; vi) supporting the education of junior and more senior medical staff; vii) designed to integrate with clinical translational research; and viii) is supporting greater connectedness for patients, families and medical staff. CONCLUSION: The UDP-WA has been initiated in the public health system to complement existing clinical genomic approaches; it has been targeted to those with a specific diagnostic need, and initiated by redirecting existing clinical and financial resources. The UDP-WA supports the provision of equitable and sustainable diagnostics and simultaneously supports capacity building in clinical care and translational research, for those with undiagnosed, typically rare, conditions.

Monitoring of Therapy for Mucopolysaccharidosis Type I Using Dysmorphometric Facial Phenotypic Signatures.

There is a pattern of progressive facial dysmorphology in mucopolysaccharidosis type I (MPS I). Advances in 3D facial imaging have facilitated the development of tools, including dysmorphometrics, to objectively and precisely detect these facial phenotypes. Therefore, we investigated the application of dysmorphometrics as a noninvasive therapy-monitoring tool, by longitudinally scoring facial dysmorphology in a child with MPS I receiving enzyme replacement therapy (ERT) and bone marrow transplantation (BMT). Both dysmorphometric measures showed a decreasing trend, and the greatest differences were found in the severity of facial discordance (Z-RMSE), displaying scores >3 SD higher than the mean at their peak, in comparison to Z-RSD scores that mostly fell within the normative range (maximum; 1.5 SD from the mean). In addition to the general trend of reduced facial dysmorphology with treatment, initial fluctuations were also evident that may have related to transient subcutaneous facial fluctuations, in the context of conditioning for bone marrow transplant. These findings support the potential of our approach as a sensitive, noninvasive, and rapid means of assessing treatment response or failure in clinical trials, and for established therapies, and would be applicable for other inherited disorders of metabolism.

A Dysmorphometric Analysis to Investigate Facial Phenotypic Signatures as a Foundation for Non-invasive Monitoring of Lysosomal Storage Disorders.

BACKGROUND: Some lysosomal storage disorders (LSDs), including Muccopolysaccharidosis type 1 (MPSI), are associated with characteristic facies. METHODS such as three-dimensional (3D) facial scanning and geometric morphometric techniques can potentially generate detailed objective descriptions of these facial phenotypes. This approach can facilitate discriminating the inherent overlap in facial phenotypes within these disease spectra, and the non-invasive monitoring of disease progression and treatment. METHODS: 3D facial images of three MPS I-affected individuals and 400 reference subjects (aged 5-25 years) were obtained using a 3dMD camera (Atlanta, Georgia). Images were fitted with an anthropometric mask, comprising a set of spatially dense quasi-landmarks. A statistical face-space was constructed from the reference image set and the MPS I-affected individuals were compared to this face-space utilising an emerging methodology known as dysmorphometrics. This facilitated simultaneous identification of harmonic and discordant facial regions. A relative significant discordance (RSD) score quantified proportional facial discordance for a given individual, whilst a root-mean-squared-error (RMSE) score measured the degree of facial discordance providing a severity measure. RESULTS: A consistent facial pattern, with differential severities, primarily affecting the frontal, nasal, infraorbital and cheek regions, was detected in all three individuals. As expected, there was greater discordance (RMSE, RSD) with clinically severe MPS I when compared to attenuated disease. CONCLUSIONS: Objective detection and localisation of MPS I facial characteristics was achieved, and severity scores were attributed. This spatially dense dysmorphometric facial phenotyping technique has the potential to be used for non-invasive treatment monitoring and as a discriminatory tool.