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PURPOSE: Penetrance estimates of Birt-Hogg-Dubé (BHD)-associated cutaneous, pulmonary, and kidney manifestations are based on clinically ascertained families. In a healthcare system population, we used a genetics-first approach to estimate the prevalence of pathogenic/likely pathogenic (P/LP) truncating variants in FLCN, which cause BHD, and the penetrance of BHD-related phenotypes. METHODS: Exomes from 135,990 patient-participants in Geisinger’s MyCode® cohort were assessed for P/LP truncating FLCN variants. BHD-related phenotypes were evaluated from electronic health records. Association between P/LP FLCN variants and BHD-related phenotypes was assessed by Firth’s logistic regression. RESULTS: P/LP truncating FLCN variants were identified in 35 individuals (1 in 3,234 unrelated individuals), 68.6% of whom had BHD-related phenotype(s) including: cystic lung disease (65.7%), pneumothoraces (17.1%), cutaneous manifestations (8.6%), and kidney cancer (2.9%). Four (11.4%) had prior clinical BHD diagnoses. CONCLUSION: In this healthcare population, the frequency of P/LP truncating FLCN variants is 60 times higher than the previously reported prevalence. Although most variant-positive individuals had BHD-related phenotypes, a minority were previously clinically diagnosed, likely because cutaneous manifestations, pneumothoraces, and kidney cancer were observed at lower frequencies than in clinical cohorts. Improved clinical recognition of cystic lung disease and education concerning its association with FLCN variants could prompt evaluation for BHD.

PURPOSE: Recurrent pathogenic copy number variants (pCNVs) have large-effect impacts on brain function and represent important etiologies of neurodevelopmental psychiatric disorders (NPDs), including autism and schizophrenia. Patterns of health care utilization in adults with pCNVs have gone largely unstudied and are likely to differ in significant ways from those of children. METHODS: We compared the prevalence of NPDs and electronic health record-based medical conditions in 928 adults with 26 pCNVs to a demographically-matched cohort of pCNV-negative controls from >135,000 patient-participants in Geisinger’s MyCode Community Health Initiative. We also evaluated 3 quantitative health care utilization measures (outpatient, inpatient, and emergency department (ED) visits) in both groups. RESULTS: Adults with pCNVs (24.9%) were more likely than controls (16.0%) to have a documented NPD. They had significantly higher rates of several chronic diseases, including diabetes (29.3% in participants with pCNVs vs. 20.4% in participants without pCNVs) and dementia (2.2% in participants with pCNVs vs. 1.0% in participants without pCNVs), and twice as many annual emergency department visits. CONCLUSION: These findings highlight the potential for genetic information – specifically, pCNVs - to inform the study of health care outcomes and utilization in adults. If, as our findings suggest, adults with pCNVs have poorer health and require disproportionate health care resources, early genetic diagnosis paired with patient-centered interventions may help to anticipate problems, improve outcomes, and reduce the associated economic burden.

Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals, a disease characteristic termed variable expressivity. Recently, the aggregate effect of common variation, quantified as polygenic scores (PGSs), has emerged as an effective tool for predictions of disease risk and trait variation in the general population. Here, we measure the effect of PGSs on 11 RGDs including four sex-chromosome aneuploidies (47,XXX; 47,XXY; 47,XYY; 45,X) that affect height; two copy-number variant (CNV) disorders (16p11.2 deletions and duplications) and a Mendelian disease (melanocortin 4 receptor deficiency (MC4R)) that affect BMI; and two Mendelian diseases affecting cholesterol: familial hypercholesterolemia (FH; LDLR and APOB) and familial hypobetalipoproteinemia (FHBL; PCSK9 and APOB). Our results demonstrate that common, polygenic factors of relevant complex traits frequently contribute to variable expressivity of RGDs and that PGSs may be a useful metric for predicting clinical severity in affected individuals and for risk stratification., Rare genetic disorders (RGDs) often exhibit significant clinical variability among affected individuals. Here, Oetjens et al. systematically study the contribution of common genetic variation to variable expressivity of RGDs and find it is frequently influenced by polygenic factors identified in genome-wide association studies of relevant traits.

Importance Cerebral palsy is a common neurodevelopmental disorder affecting movement and posture that often co-occurs with other neurodevelopmental disorders. Individual cases of cerebral palsy are often attributed to birth asphyxia; however, recent studies indicate that asphyxia accounts for less than 10% of cerebral palsy cases. Objective To determine the molecular diagnostic yield of exome sequencing (prevalence of pathogenic and likely pathogenic variants) in individuals with cerebral palsy. Design, Setting, and Participants A retrospective cohort study of patients with cerebral palsy that included a clinical laboratory referral cohort with data accrued between 2012 and 2018 and a health care–based cohort with data accrued between 2007 and 2017. Exposures Exome sequencing with copy number variant detection. Main Outcomes and Measures The primary outcome was the molecular diagnostic yield of exome sequencing. Results Among 1345 patients from the clinical laboratory referral cohort, the median age was 8.8 years (interquartile range, 4.4-14.7 years; range, 0.1-66 years) and 601 (45%) were female. Among 181 patients in the health care–based cohort, the median age was 41.9 years (interquartile range, 28.0-59.6 years; range, 4.8-89 years) and 96 (53%) were female. The molecular diagnostic yield of exome sequencing was 32.7% (95% CI, 30.2%-35.2%) in the clinical laboratory referral cohort and 10.5% (95% CI, 6.0%-15.0%) in the health care–based cohort. The molecular diagnostic yield ranged from 11.2% (95% CI, 6.4%-16.2%) for patients without intellectual disability, epilepsy, or autism spectrum disorder to 32.9% (95% CI, 25.7%-40.1%) for patients with all 3 comorbidities. Pathogenic and likely pathogenic variants were identified in 229 genes (29.5% of 1526 patients); 86 genes were mutated in 2 or more patients (20.1% of 1526 patients) and 10 genes with mutations were independently identified in both cohorts (2.9% of 1526 patients). Conclusions and Relevance Among 2 cohorts of patients with cerebral palsy who underwent exome sequencing, the prevalence of pathogenic and likely pathogenic variants was 32.7% in a cohort that predominantly consisted of pediatric patients and 10.5% in a cohort that predominantly consisted of adult patients. Further research is needed to understand the clinical implications of these findings.

Aim: We sought to identify potential pleiotropy involving pharmacogenes. Methods: We tested 184 functional variants in 34 pharmacogenes for associations using a custom grouping of International Classification and Disease, Ninth Revision billing codes extracted from deidentified electronic health records of 6892 patients. Results: We replicated several associations including ABCG2 (rs2231142) and gout (p = 1.73 × 10-7; odds ratio [OR]: 1.73; 95% CI: 1.40–2.12); and SLCO1B1 (rs4149056) and jaundice (p = 2.50 × 10-4; OR: 1.67; 95% CI: 1.27–2.20). Conclusion: In this systematic screen for phenotypic associations with functional variants, several novel genotype–phenotype combinations also achieved phenome-wide significance, including SLC15A2 rs1143672 and renal osteodystrophy (p = 2.67 × 10- 6; OR: 0.61; 95% CI: 0.49–0.75).

Population stratification or confounding by genetic ancestry is a potential cause of false associations in genetic association studies. Estimation of and adjustment for genetic ancestry has become common practice thanks in part to the availability of ancestry informative markers on genome-wide association study (GWAS) arrays. While array data is now widespread, these data are not ubiquitous as several large epidemiologic and clinic-based studies lack genome-wide data. One such large epidemiologic-based study lacking genome-wide data accessible to investigators is the National Health and Nutrition Examination Surveys (NHANES), population-based cross-sectional surveys of Americans linked to demographic, health, and lifestyle data conducted by the Centers for Disease Control and Prevention. DNA samples (n=14,998) were extracted from biospecimens from consented NHANES participants between 1991-1994 (NHANES III, phase 2) and 1999-2002 and represent three major self-identified racial/ethnic groups: non-Hispanic whites (n=6,634), non-Hispanic blacks (n=3,458), and Mexican Americans (n=3,950). We as the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study genotyped candidate gene and GWAS-identified index variants in NHANES as part of the larger Population Architecture using Genomics and Epidemiology (PAGE) I study for collaborative genetic association studies. To enable basic quality control such as estimation of genetic ancestry to control for population stratification in NHANES san genome-wide data, we outline here strategies that use limited genetic data to identify the markers optimal for characterizing genetic ancestry. From among 411 and 295 autosomal SNPs available in NHANES III and NHANES 1999-2002, we demonstrate that markers with ancestry information can be identified to estimate global ancestry. Despite limited resolution, global genetic ancestry is highly correlated with self-identified race for the majority of participants, although less so for ethnicity. Overall, the strategies outlined here for a large epidemiologic study can be applied to other datasets accessible for genotype phenotype studies but are sans genome-wide data.

Coordination of fetal maturation with birth timing is essential for mammalian reproduction. In humans, preterm birth is a disorder of profound global health significance. The signals initiating parturition in humans have remained elusive, due to divergence in physiological mechanisms between humans and model organisms typically studied. Because of relatively large human head size and narrow birth canal cross-sectional area compared to other primates, we hypothesized that genes involved in parturition would display accelerated evolution along the human and/or higher primate phylogenetic lineages to decrease the length of gestation and promote delivery of a smaller fetus that transits the birth canal more readily. Further, we tested whether current variation in such accelerated genes contributes to preterm birth risk. Evidence from allometric scaling of gestational age suggests human gestation has been shortened relative to other primates. Consistent with our hypothesis, many genes involved in reproduction show human acceleration in their coding or adjacent noncoding regions. We screened >8,400 SNPs in 150 human accelerated genes in 165 Finnish preterm and 163 control mothers for association with preterm birth. In this cohort, the most significant association was in FSHR, and 8 of the 10 most significant SNPs were in this gene. Further evidence for association of a linkage disequilibrium block of SNPs in FSHR, rs11686474, rs11680730, rs12473870, and rs1247381 was found in African Americans. By considering human acceleration, we identified a novel gene that may be associated with preterm birth, FSHR. We anticipate other human accelerated genes will similarly be associated with preterm birth risk and elucidate essential pathways for human parturition., Children's Discovery Institute, March of Dimes Birth Defects Foundation, National Institute of General Medical Sciences (U.S.) (T32 GM081739), Washington University (Saint Louis, Mo.), Washington University (Saint Louis, Mo.) (Mr. and Mrs. Spencer T. Olin Fellowship for Women in Graduate Study), Sigrid Jusélius stiftelse, Signe and Anne Gyllenberg Foundation, Academy of Finland