Rolf Stottmann, PhD

Gpr63 is a modifier of microcephaly in Ttc21b mouse mutants

Many human diseases can have variable presentations based on underlying genetic differences. TTC21B in humans is a known ciliopathy gene. Mice homozygous for a null allele of Ttc21b also have a spectrum of ciliopathy phenotypes, including microcephaly (small brain) which varies in severity on different backgrounds. As an initial attempt to understand the mechanism(s) underlying the variable effects on brain size, we performed a quantitative trait locus (QTL) analysis and found two regions of genomic significance that correlated with smaller brain size. We confirmed both QTLs with congenic lines and hypothesized Gpr63 might be a contributing locus for one of these. We evaluated this hypothesis directly by using genome editing. Thus, we combined classical QTL analysis and genome editing to directly test the resulting hypothesis. This is likely to be a widely applicable resurgence of classical mouse genetics to understand human disease.

Ying Sun, PhD

Intravenous infusion of iPSC-derived neural precursor cells increases acid beta-glucosidase function in the brain and lessens the neuronopathic phenotype in a mouse model of Gaucher disease

Approved enzyme replacement therapy with a limitation in crossing the blood-brain barrier is only effective on visceral manifestations for Gaucher disease patients, but is completely ineffective for neuronopathic variants that affect the central nervous system (CNS) present often early in life and result in high mortality. A novel complex, SapC-DOPS nanovesicles, has the ability to cross the blood-brain barrier and selectively target neuronal tissue, thereby providing a biological vehicle for delivering acid beta-glucosidase (GCase) into the central nervous system. SapC-DOPS-GCase as a novel therapeutic approach corrected GCase deficiency in brain cells and tissues and showed efficacy in reducing brain inflammation and neurological phenotypes in the mouse model of neuronopathic Gaucher disease. This study established a new mechanism of CNS targeting of SapC-DOPS through a specific phosphatidylserine receptor and lymphatic circulation system.CNS-selective delivery system using SapC-DOPS nanovesicles provides a new strategy for treating neuronopathic Gaucher disease.

Michael Pauciulo, PhD

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension

This study used a cohort of 2572 pulmonary arterial hypertension (PAH) patients from the PAH Biobank at Cincinnati Children’s to investigate epigenetic dysregulation and altered DNA methylation in PAH. Exome sequencing data on 1832 unrelated PAH Biobank patients of European descent showed increased burden of deleterious variants in the tet-methylcytosine-dioxygenase-2 (TET2) gene, a key enzyme in DNA demethylation, when compared to 7509 European controls from the Genome Aggregation Database (gnomAD). Researchers found hemodynamic and histological evidence of spontaneous PAH also in TET2 knockout mice. Our paper is the first to link epigenetics to PAH pathogenesis and suggests decreased TET2 expression as a biomarker for PAH.

Melanie Myers, PhD, MS, CGC

Adolescents' and Parents' Genomic Testing Decisions: Associations With Age, Race, and Sex

There has been a longstanding ethical principle to only test children for genetic conditions that can be monitored, prevented, or treated during childhood. However, when the American College of Medical Genetics and Genomics (ACMG) challenged this perspective by recommending mandatory opportunistic analysis and return of a subset of genes, including some for adult-onset conditions, regardless of patient age when performing genome sequencing for clinical purposes. We examined 163 adolescents’ and their parents’ decisions about learning actual genomic research results for the adolescent. Adolescents unselected for clinical indication chose to learn less genomic information than their parents. In addition, black adolescents were less likely to choose to learn all results than white adolescents, and parents were less likely to choose to learn all results for their daughters than their sons. Rather than relying solely on parents’ decisions, facilitated shared decision-making should be in place as opportunities to learn genomic information in clinical and research settings become increasingly available.

Nicole Weaver, MD

Comparison of Evolution of Aortic Root Dilation and Ghent Criteria in Preadolescents and Adolescents with and without Marfan Syndrome

Marfan syndrome is a genetic connective tissue disease associated with age-related progressive risk for aortic dilation and dissection. Readily observable physical features of Marfan syndrome, such as tall stature, scoliosis, and stretch marks, frequently become apparent during adolescence. Developed for adults, the Ghent criteria (2010) for clinical diagnosis of Marfan syndrome, it has previously been unclear whether application of Ghent criteria is useful to exclude a diagnosis of Marfan syndrome in preadolescents and adolescents. This study demonstrated that the Ghent criteria (2010) is useful to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age.