Education, Research, Patient Care qd

Undiagnosed Rare Congenital Disorders

Rare Genetic Disorders Of Infants And Neonates
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 our Center. 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. 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.

Task Force For Neonatal Genomics (TFNG)
The TFNG was created in 2012 to help meet the enormous unmet need of families with acute, likely genetic disorders. In sharp contrast to other national and international efforts, the TFNG 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. The TFNG is composed of a group of physicians, nurses, genetic counselors, geneticists, and cell biologists. Recruiting families from nine (9) Duke pediatric specialty clinics, 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. 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.

Congenital Anomalies Of The Kidney And Urogenital Tract
Through dedicated support from the National Institute of Diabetes and Digestive and Kidney Disorders, the CHDM 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 pathomechanism at the cellular level. Importantly, through a dedicated TFNG Pilot Program, this activity has also served as an opportunity to host young physicians and basic scientists to generate proof of concept studies and to gain critical skills. 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 every day life.

Contiguous Gene Syndromes
Among the genetic disorders discussed in other sections, the CHDM 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 CHDM 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 [22596160, 25439725, 24746959, 24140112]. Looking forward, our investigators are working to dissect dozens more CNVs, including lesions that affect multiple megabases and manifest complex clinical pathologies, such as DiGeorge syndrome and the TAR/1q21.2 region.

Identification Of Suppressors As Therapeutic Targets
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 CHDM 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 [26280580]. We aspire to systematize this approach for numerous disorders for which we might have the opportunity to provide ameliorating or therapeutic leads.

Structural Neuroanatomical Defects In Neonates And Young Children
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 Center 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 [25865493, 25834187, 25597510]. 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, as well as genetic mechanisms that had never before been described with the description of cis-complementation being such an example [23656588].