Research Overview

We are broadly interested in the discovery, functional analysis, and therapeutic targeting of genes that are altered in human disease.  We seek to understand how different types of genetic changes affect the function of human genes and influence the molecular phenotype within a single cell.  By understanding the underlying function of a genetic mutation at its fundamental level, we can identify potential targeted therapies for a wide variety of clinical diseases.

Our research lab leverages genomic tools to understand how both rare and common human genetic variation contribute to and cause human disease.  As the sequencing technology has matured, one of the major challenges in genomics is interpreting the majority of the DNA base pairs that are sequenced within an individual -- an important next step in integration of research findings into the clinical setting.

The lab takes a bidirectional approach. First, we are interested in rare genetic syndromes caused by genetic changes in genes that function to organize DNA through chromatin modification.  The lab leverages functional genomic approaches (RNA-seq, ChIP-seq, methylation-seq) to 1) understand how rare deleterious mutations in chromatin modifiers affect downstream pathways and human development in a cellular model system,  2) identify modifiers of disease severity and 3) prioritize putative drug targets. Second, we are also interested in the shared genetic basis of monogenic and complex diseases. We are using existing large scale GWAS data sets to better identify and interpret findings by leveraging the extremes of the phenotypic spectrum (monogenic/Mendelian disease). 

Our current focus is on genetic syndromes that are due to rare mutations in genes that are important for chromatin conformation (a.k.a. chromatin modifiers). 

Correlation Between Mendelian and Complex Traits

Monogenic Mendelian syndromes, although individually rare, constitute a large burden on families and the health care system. Such disorders are caused by rare genetic variants that disrupt protein-coding genes to cause disease. In contrast, common diseases (affecting more than 5% of the population) are polygenic and likely caused by non-coding variants, most of which do not alter the protein and therefore likely regulate gene expression.

Emerging precision medicine initiatives focus on individualized diagnosis, prognosis and treatment based on the integration of clinical, genomic, epigenetic, and other biomarkers. Our lab seeks to advance these goals in the setting of rare Mendelian syndromes. While precision medicine has been wildly successful in providing genetic diagnoses through clinical whole exome sequencing, it has left in its wake a gap between our expanded diagnostic capability and our ability to provide therapies based on the genetic diagnosis.

The majority of patients now have a genetic diagnosis that ends the “diagnostic odyssey”, but leave clinicians with vexing questions regarding prognosis and treatments based on the genetic diagnosis. Our lab seeks to bridge this gap, leveraging both publically available data for a wide variety of complex diseases and functional genomic data generated from samples in patients with rare monogenic disease. 

 

Interrogating the functional consequences of genetic diseases due to mutations in chromatin modifiers.

Disrupted genes in Mendelian syndromes have large effects on downstream targets, contributing to the multitude of syndromic features. One or more of these gene targets may affect the risk of common disease (Figure 1). Recent studies have demonstrated a combinatorial effect of Mendelian syndromes on risk of common disease [5, 6], but until recently, with the advent of high throughput sequencing, we have not had the ability to systematically detect these interactions within an individual patient. While the relationship between Mendelian syndromes and common diseases acts through multiple layers of cellular regulation, this proposal represents a focused approach to study interactions at the level of transcriptional regulation. Understanding the joint influence of monogenic mutations and common disease variants on disease phenotypes allows us to unravel the underlying biological processes contributing to human disease.

KAT6A 

 

Understanding the role of chromatin  modifiers in human development and disease started several years ago when I led a study first describing a novel genetic syndrome with global developmental delay and syndromic features that were caused by rare de novo mutations in the gene KAT6A.  The KAT6A gene's major role is to acetylate histones and other proteins within a cell, allowing for the proper expression of RNA and proteins during human development. Within 2 years of publication, there are over 100 individuals known to be diagnosed with mutations in KAT6A, making it one of the more common causes of syndromic developmental delay. 

We have an active research program around KAT6A and related genes, as mutations in chromatin modifier genes typically have similar features, suggesting a related etiology. 

[More to come here]

 

Link to Patient Survey

 

For patients, a great resource is that KAT6A Foundation

 

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If you are interested in contacting Valerie Arboleda to hear about the labs on going research studies and how you might become involved, please fill out the form below. 

At the intersection between research and clinical diagnosis, I am interested in developing clinical-grade genomic testing for human disease. I am particularly interested in translating genomic findings in cancer, pharmacogenomics, and complex diseases to guide individualized diagnosis, prognosis and therapeutic decisions. 

In my training, I pioneered early work exploring the utility of targeted next-generation sequencing and then exome sequencing for the rapid genetic diagnosis of disorders of sex development (DSD). Through the use of targeted exome sequencing we increased the rate of genetic diagnosis in DSD to nearly 40% of patients, thus significantly shortening the diagnostic odyssey. This work led us to propose a novel, genetics-centered approach within pediatric genetics and endocrinology, where genetic testing would be performed as an initial screening test. Identification of a novel variant would be followed by clinical confirmatory testing to validate the effect of the mutation in the patient. Confirmatory tests would be based on the predicted effect of the mutation on endocrinologic and metabolic pathways. This would limit the number of invasive and stressful stimulatory testing commonly done to obtain a DSD diagnosis.