Hakon Hakonarson

PurposeRNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations.MethodsPatients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts.ResultsWe identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals …

PurposePersistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI.MethodsWe conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI.ResultsThe inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive …

Study Objectives To identify genetic susceptibility variants in pediatric obstructive sleep apnea in European American and African American children. Methods A phenotyping algorithm using electronic medical records was developed to recruit cases with OSA and control subjects from the Center for Applied Genomics at Children’s Hospital of Philadelphia (CHOP). Genome-wide association studies (GWAS) were performed in pediatric OSA cases and control subjects with European American (EA) and African American (AA) ancestry followed by meta-analysis and sex stratification. Results The algorithm accrued 1486 subjects (46.3% European American, 53.7% African American). We identified genomic loci at 1p36.22 and 15q26.1 that associated with OSA risk in EA and AA, respectively. We also revealed a shared risk locus at 18p11.32 (rs114124196, p …

Methods and uses for diagnosing and treating anxiety disorders are encompassed, wherein diagnosis and treatment may be based upon an assessment of genetic alterations in metabotropic glutamate receptor (mGluR) network genes and wherein treatment is with nonspecific activators of mGluRs such as fasoracetam.

CD8+ T cell dysfunction impedes anti-tumor immunity in solid cancers but the underlying mechanisms are diverse and poorly understood. Extracellular matrix (ECM) composition has been linked to impaired T cell migration and enhanced tumor progression; however, impacts of individual ECM molecules on T cell function in the tumor microenvironment (TME) are only beginning to be elucidated. Upstream regulators of aberrant ECM deposition and organization in solid tumors are equally ill-defined. Therefore, we investigated how ECM composition modulates CD8+ T cell function in undifferentiated pleomorphic sarcoma (UPS), an immunologically active desmoplastic tumor. Using an autochthonous murine model of UPS and data from multiple human patient cohorts, we discovered a multifaceted mechanism wherein the transcriptional co-activator YAP1 promotes collagen VI (COLVI) deposition in the UPS TME. In …

ObjectivesHeterozygous missense variants in MYBPC1 have been recently identified in 13 patients from 6 families with congenital myopathy with tremor. All the patients had mild skeletal myopathy invariably associated with a distinctive myogenic tremor and hypotonia with gradual clinical improvement. However, no phenotypic description has been reported for the neonatal respiratory impairment that patients may suffer.MethodsWe report 3 new patients from 2 independent families with congenital myopathy with tremor.ResultsTremors and respiratory distress associated with stridor should raise the diagnosis of congenital myopathy with tremors linked to MYBPC1-dominant variants in children with neonatal hypotonia.DiscussionNeonatal severe respiratory impairment requiring intensive noninvasive ventilation because of stridor is described in 2 patients. Stridor was previously reported in one other case and is part …

Genetic effects on changes in human traits over time are understudied and may have important pathophysiological impact. We propose a framework that enables data quality control, implements mixed models to evaluate trajectories of change in traits, and estimates phenotypes to identify age-varying genetic effects in genome-wide association studies (GWASs). Using childhood body mass index (BMI) as an example, we included 71,336 participants from six cohorts and estimated the slope and area under the BMI curve within four time periods (infancy, early childhood, late childhood and adolescence) for each participant, in addition to the age and BMI at the adiposity peak and the adiposity rebound. GWAS on each of the estimated phenotypes identified 28 genome-wide significant variants at 13 loci across the 12 estimated phenotypes, one of which was novel (in DAOA) and had not been previously associated with childhood or adult BMI. Genetic studies of changes in human traits over time could uncover novel biological mechanisms influencing quantitative traits.

BackgroundPubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.ResultsLarge-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify …