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• Kids First: Genomic Studies of Orofacial Cleft Birth Defects

  The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource). Both childhood cancers and structural birth defects are critical and costly conditions associated with substantial morbidity and mortality. Elucidating the underlying genetic etiology of these diseases has the potential to profoundly improve preventative measures, diagnostics, and therapeutic interventions. WGS and phenotypic data from this study are accessible through dbGaP and kidsfirstdrc.org, where other Kids First datasets can also be accessed. The Kids First study of nonsyndromic orofacial cleft birth defects (OFCs) is a whole genome sequencing study of 415 White parent-case trios drawn from ongoing collaborations led by Dr. Mary L. Marazita of the University of Pittsburgh Center for Craniofacial and Dental Genetics, including collaborations with Dr. George Wehby of the University of Iowa, Dr. Jacqueline Hecht of the University of Texas, and Dr. Terri Beaty of Johns Hopkins University. Sequencing was done by the Washington University McDonell Genome Institute. The case in each of the Kids First trios has cleft lip (CL, Figure A), cleft palate (CP, Figure B), or both (CL+CP, Figure C): OFCs are genetically complex structural birth defects caused by genetic factors, environmental exposures, and their interactions. OFCs are the most common craniofacial anomalies in humans, affecting approximately 1 in 700 newborns, and are one of the most common structural birth defects worldwide. On average a child with an OFC initially faces feeding difficulties, undergoes 6 surgeries, spends 30 days in hospital, receives 5 years of orthodontic treatment, and participates in ongoing speech therapy, leading to an estimated total lifetime treatment cost of about $200,000. Further, individuals born with an OFC have higher infant mortality, higher mortality rates at all other stages of life, increased incidence of mental health problems, and higher risk for other disorders (notably including breast, brain, and colon cancers). Prior genome-wide linkage and association studies have now identified at least 18 genomic regions likely to contribute to the risk for nonsyndromic OFCs. Despite this substantial progress, the functional/pathogenic variants at OFC-associated regions are mostly still unknown. Because previous OFC genomic studies (genome-wide linkage, genome-wide association studies (GWAS), and targeted sequencing) are based on relatively sparse genotyping data, they cannot distinguish between causal variants and variants in linkage disequilibrium with unobserved causal variants. Moreover, it is unknown whether the association or linkage signals are due to single common variants, haplotypes of multiple common variants, clusters of multiple rare variants, or some combination. Finally, we cannot yet attribute specific genetic risk to individual cases and case families. Therefore, the goal of the current study is to identify specific OFC risk variants in Whites by performing whole genome sequencing of parent-case trios.

  Study phs001168

• Idiopathic Scoliosis (SNP-array & WES study)

  This study aimed to investigate the genetic basis of severe idiopathic scoliosis (IS) using whole exome sequencing (WES) and SNP array methods. We intended to identify structural and point genetic variations contributing to the development of IS. By analyzing intraoperatively collected articular processes (AP) and blood (BL) samples from 70 unrelated individuals with IS, we sought to uncover pathogenic copy number variants (CNVs), regions of homozygosity (ROH), and single-nucleotide variants (SNVs) linked to the condition. EGAD00001015758

  Study EGAS00001008152

• Center for Common Disease Genomics [CCDG] - Cardiovascular ATVB: Atherosclerosis Thrombosis and Vascular Biology

  Italian Atherosclerosis Thrombosis and Vascular Biology study is a prospective, nationwide, case-control study involving 125 coronary care units in Italy. The cases were patients who were hospitalised for a first MI before the age of 45 years and underwent coronary angiography. Acute MI was defined as resting chest pain lasting more than 30 minutes, accompanied by persistent electrocardiographic changes, and confirmed by an increase in total creatine kinase or in the MB fraction to more than twice the upper normal limits. The controls were healthy subjects without a history of thromboembolic disease who were unrelated to the patients, but individually matched with them by age, gender and geographical origin. They were enrolled from among the blood donors or staff of the same participating hospitals. Recruitment of cases and controls took place between 1994 and 2007. This site hosts data from ~60 whole exomes.

  Study phs001592

• Center for Common Disease Genomics (CCDG) - Cardiovascular: eMERGE - Northwestern Cohort

  The National Human Genome Research Institute (NHGRI) has funded the Centers for Common Disease Genomics (CCDG), a collaborative large-scale genome sequencing effort to comprehensively identify rare risk and protective variants contributing to common disease phenotypes and to better understand the general principles of genomic architecture underlying common, complex inherited diseases. This study contains variant calls derived from the whole genome sequence data of an early-onset coronary artery disease case-control cohort selected from the NUgene Project biobank at Northwestern University. Case status was assigned based on the presence of myocardial infarction, coronary artery stenosis greater than 70% in at least one coronary artery, and/or revascularization (coronary angioplasty with or without stent placement or coronary artery bypass grafting) at an early age. In this study "early age" is defined as men 60 years of age or younger and women 70 years of age or younger.

  Study phs001913

• Spatiotemporal Charting of Human Esophageal Development for Epidermolysis Bullosa Cell Therapy

  Human fetal esophageal development is not well understood. We present a spatio-temporal single-cell multi-omics atlas to close such a long-standing knowledge gap. With such an atlas, we describe the cellular heterogeneity and lineage transitions of esophageal epithelium and stroma. We delineate the cellular dynamics of both epithelial and stromal populations during the establishment of esophageal tissue architecture. We identify niche paracrine signals that drive the development of the epithelium. We develop an in silico perturbation deep learning algorithm to further enlighten the in vitro derivation of esophageal basal cells (eBCs) and we use the algorithm to screen for effective and efficient signaling pathway perturbations that could guide in vitro eBC differentiation. We observe that chemically perturbing prioritized pathways yields functional eBCs. Such success sheds light on cell replacement therapy of eBC dysfunction, such as Epidermolysis Bullosa.

  Study phs003281

• Ensilication as a Cold‑Chain–Free Solution for High‑Fidelity DNA Preservation in tumor samples

  Nucleic acid preservation requires continuous refrigeration at -20 °C to -80 °C, creating infrastructure barriers limiting genomic medicine access globally. While ambient-temperature preservation methods exist, their effects on DNA integrity and sequence fidelity remain incompletely characterized. The project aims to evaluate ensilication as a method for preserving DNA at ambient temperatures and to determine whether it can match or exceed the fidelity of conventional ultra‑low‑temperature storage. It seeks to assess the technology’s ability to maintain diagnostic accuracy, including detection of clinically actionable variants in tumor samples. Another goal is to compare sequencing‑related artifact rates between ensilicated and cryogenically stored DNA to quantify improvements in data quality. Ultimately, the project aims to establish ensilication as a cold‑chain‑independent solution that enables more accessible global genomic testing and biobanking.

  Study EGAS50000001698

• Combined MEK and BCL-2/XL inhibition is effective in high-grade serous ovarian cancer patient-derived xenograft models and BIM levels are predictive of responsiveness

  Most patients with late stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, thus making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient-derived xenograft (PDX) models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the pro-apoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death and displayed synergy in vitro in most models. In vivo, the GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models – those with high BIM at baseline that was increased with MEK inhibition and those with low basal Bim and high pERK levels. Models with low BIM and low pERK were non-responsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.

  Dataset EGAD00001005111

• Characterization and clinical relevance of the genomic alterations defining invasive lobular breast cancer

  Background: Invasive lobular breast cancer (ILBC) is the second most common histological subtype after ductal breast cancer (IDBC). In spite of significant clinical and pathological differences, ILBC is still treated as IDBC. Here, we aimed at identifying recurrent genomic alterations in ILBC with potential clinical implications.Methods: Starting from 630 ILBC primary tumors with a median follow up of 10 years, we interrogated oncogenic substitutions and indels of 360 cancer genes and genome-wide copy number alterations in 413 and 170 ILBC samples, respectively, and correlated those findings with clinical, pathological, and outcome features. The Cancer Genome Atlas database was used for comparison of frequency estimates.Results: Besides the high mutation frequency of CDH1 in 65% of the tumors, alterations in one of the three key genes of the PI3K pathway, PIK3CA, PTEN and AKT1, were present in more than half of the cases. ERBB2 and ERBB3 were mutated in 5.1 and 3.6% of the tumors. FOXA1 mutations and ESR1 copy number gains were detected in 9% and 25% of the samples. All these alterations were more frequent in ILBC than IDBC. The histological diversity of ILBC was associated with specific genomic alterations, such as enrichment for ERBB2 mutations in the mixed, non-classic subtype, and for ARID1A mutations and ESR1 gains in the solid subtype. Finally, ERBB2 and AKT1 mutations were associated with short-term risk of relapse, and chromosome 1q and 11p gain with increased and decreased breast cancer free survival, respectively.Conclusion: ERBB2, ERBB3 and AKT1 mutations represent high prevalence therapeutic targets in ILBC. FOXA1 mutations and ESR1 gains urgently deserve dedicated clinical investigation, especially in the context of endocrine treatment.

  Dataset EGAD00001001395

• Genetic Basis of Developmental Disabilities

  Developmental disabilities are birth defects that cause lifelong problems with how a body part or system works. Developmental disabilities include nervous system insults affecting how the brain, spinal cord and nervous system function; they cause intellectual disability, including Down syndrome and fragile X syndrome; and they also cause learning and behavioral disorders, such as autism spectrum disorders. At the Kennedy Krieger Institute, approximately 450 inpatients and 13,000 outpatients are seen per year (involving 114,000 visits). For most of these disorders, the underlying molecular cause has not been identified. Some, such as chromosomal disorders, have a strongly genetic basis while others, such as traumatic brain injury, are caused by environmental insults but are nonetheless influenced by the genetic background. The purpose of the present study is to identify chromosomal abnormalities underlying a variety of developmental disabilities. The approach is to obtain blood and saliva from children, and from one or both biological parents (and in some cases from siblings and/or additional relatives). Genomic DNA is purified and assayed on single nucleotide polymorphism (SNP) microarrays and/or by sequencing, including whole genome sequencing. These technologies provide high resolution information about chromosomal changes, and the information provided by the parental (and other relatives') DNA allows an interpretation of whether changes in a child are inherited or occur de novo. The study design includes multiple data analysis procedures to interpret the biological significance of findings of chromosomal changes relative to a child's parents, relative to children with similar diagnoses, relative to children with other chromosomal anomalies, and (in some cases) relative to the chromosomal status of siblings. We will further interpret the significance of the findings relative to the general (apparently normal) population by obtaining publicly available data from apparently normal individuals.

  Study phs000337

• Genetic Epidemiology Network of Arteriopathy (GENOA)

  The Genetic Epidemiology Network of Arteriopathy (GENOA) is one of four networks in the NHLBI Family-Blood Pressure Program (FBPP). GENOA's long-term objective is to elucidate the genetics of target organ complications of hypertension, including both atherosclerotic and arteriolosclerotic complications involving the heart, brain, kidneys, and peripheral arteries. The longitudinal GENOA Study recruited European-American and African-American sibships with at least 2 individuals with clinically diagnosed essential hypertension before age 60 years. All other members of the sibship were invited to participate regardless of their hypertension status. Participants were diagnosed with hypertension if they had either 1) a previous clinical diagnosis of hypertension by a physician with current anti-hypertensive treatment, or 2) an average systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg based on the second and third readings at the time of their clinic visit. The Family Blood Pressure Program (FBPP), GENOA's parent program, is an unprecedented collaboration to identify genes influencing blood pressure (BP) levels, hypertension, and its target-organ damage. This program has conducted over 21,000 physical examinations, assembled a shared database of several hundred BP and hypertension-related phenotypic measurements, completed genome-wide linkage analyses for BP, hypertension, and hypertension associated risk factors and complications, and published over 130 manuscripts on program findings. The FBPP emerged from what was initially funded as four independent networks of investigators (HyperGEN, GenNet, SAPPHIRe and GENOA) competing to identify genetic determinants of hypertension in multiple ethnic groups. Realizing the greater likelihood of success through collaboration, the investigators created a single confederation with program-wide and network-specific goals.

  Study phs001238