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Despite their misnaming, rare genetic disorders represent a major burden, with profound consequences to both families and the strained health care system. Structural birth defects, a significant fraction of which are underscored by genetic mutations, have been established consistently as the leading cause of mortality in the first postnatal year. The improved diagnosis and management of young children with pediatric genetic disorders is a high research priority for the ACT-GeM. Although many major medical centers in the world employ next-generation sequencing paradigms as a first-pass diagnostic tool to uncover the genetic basis of ultra-rare disorders, our program layers functional analyses onto genome findings with a suite of zebrafish assays, cellular studies and, as necessary, mouse models, to determine biological relevance and variant pathogenicity. These models have emerged as powerful tools to both understand disease mechanism and also serve as novel platforms for therapeutic development [Francescatto and Katsanis 2015]. Our interest in rare congenital disorders is broad, but involves a prerequisite for structural organ defects whose phenotype can be captured quantitatively. Through interactions and collaborations with academic colleagues; patient support groups; and partners from the pharmaceutical industry, we recruit and study the genetic architecture and pathomechanisms of patients with a variety of suspected genetic disorders.
The TFNG was created in 2012 to help meet the enormous unmet need of families with acute, likely genetic disorders. This effort focuses primarily on the first years of life (0-5 years), with a view of accelerating diagnosis; improving the time window of therapeutic intervention; and transforming the relationship between physicians and patients into an iterative partnership [Katsanis et al, 2018]. The TFNG is composed of a group of physicians, nurses, genetic counselors, geneticists, and cell biologists. With almost ten years of continuous effort and experience from Duke University, the TFNG executes cutting edge genomics coupled with functional assays to identify rare mutations that contribute to acute genetic disorders in neonates and young children [Jordan et al, 2015, Helbig et al, 2018, Khan et al, 2019]. Based on the recruitment tools, analytic pipelines and functional assays developed on an existing cohort of participants enrolled at Duke University, we are now actively enrolling research participant families from Lurie Children’s. Our work strives to improve the delivery of diagnostics to families in need while at the same time serving as a platform for both discovery and novel therapeutic opportunities.
Through dedicated support from the National Institute of Diabetes and Digestive and Kidney Disorders, the ACT-GeM leads a segment of the TFNG dedicated exclusively to the recruitment, genomic and functional analysis and return of results to pediatric patients with structural defects of the renal and urogenital tract. Through substantial cross-fertilization with other components of the study, this team has worked to improve the genetic diagnosis of young children with such pathologies, while at the same time informing new genetic architecture and pathomechanisms at the cellular level. For example, we performed genetic and functional dissection of the DiGeorge Syndrome locus to identify CRKL as the main genetic driver [Lopez-Rivera et al, 2017]. Additionally, we expanded the phenotypic spectrum of condesinopathies by identifying and producing a in vivo model for individuals harboring disruptive mutations in NCAPG2 [Khan et al, 2019]. We and others also demonstrated that deleterious variants in GREB1L are implicated in the pathogenesis of renal agenesis and hypodysplasia [Sanna-Cherchi et al, 2017]. Finally, through our TFNG Educational Program, we have engaged the broader physician and patient community to come together to understand common needs, hopes, fears and aspirations regarding the impact of genomic data to everyday life.
Among the genetic disorders discussed in other sections, the ACT-GeM has placed particular emphasis on copy number variants. These genetic lesions are substantial contributors to both rare and common genetic disorders yet have proven challenging to study, in part because they affect the copy number and expression levels of several, sometimes dozens, of genes. To help overcome these issues, the ACT-GeM is continuously developing functional tools to understand: (a) what genes within chromosomal deletions/duplications are the major drivers of pathology; and (b) what is the genetic architecture of copy number variations (CNVs) in terms of the contribution of other genes. Using such approaches, we have made substantial progress in identifying potent drivers of numerous CNVs of varying size [Golzio et al, 2012, Carvalho et al, 2014, Dauber et al, 2013]. Furthermore, were able to dissect genetic drivers of kidney defects in the DiGeorge syndrome [Lopez-Rivera et al, 2017], identify genetic interactions between KCTD13 and ciliary genes, suggesting a role for ciliary dysfunction 16p11.2 600 kb BP4-BP5 pathology [Migliavacca et al, 2015] and strong evidence for the contribution of driver genes and genetic interactions on craniofacial and neuroanatomical phenotypes in 16p11.2 [Qiu et al, 2019, Loviglio et al, 2017).
Recent technological improvements have empowered the efficient manipulation of gene expression and the genome itself. Using a combination of RNAi and CRISPR in cells and zebrafish embryos, the ACT-GeM is leading the search for the identification of suppressors of human genetic diseases, in other words, genes whose ablation or attenuation might have therapeutic benefit to the phenotypes driven by other genetic and genomic lesions. Our work shows early promise with the identification of suppressors for a subset of ciliopathies and RASopathies, which have in turn opened possibilities for the testing of lead therapeutic compounds [Bögershausen et al, 2015, Tsai et al, 2018]. We aspire to systematize this approach for numerous disorders for which we might have the opportunity to provide ameliorating or therapeutic leads.
Rare disorders that result in central and/or peripheral nervous system abnormalities are usually seen in less than 0.1% of the general healthy population. The ACT-GeM has investigated a wide spectrum of such disorders that though rare, potentially hold the key to mechanisms that apply to a plethora of other conditions with similar clinical presentations [Niceta et al, 2015, Borck et al, 2015, Wortmann et al, 2015, Frints et al, 2018, Niihori et al, 2019, Ansar et al, 2019, Helbig et al, 2018]. Additionally, the study of rare disorders lends the possibility to further broaden our knowledge of unanticipated biological phenomena, such as instances of digenic and/or oligogenic inheritance [Margolin et al, 2013, Khan et al, 2019]; genetic mechanisms that had never before been described with the description of cis-complementation being such an example [Jordan et al, 2015]; pleiotropic effects derived from a single locus [Shaw et al, 2017]; divergent variant pathogenicity that is splice-isoform dependent [Sarparanta et al, 2012, Schulte et al, 2014, Borck et al, 2015]; and duality of mutational effects that determine phenotypic outcome [Guissart et al, 2018].