RESUMO
To understand the genetic contribution to primary pediatric cardiomyopathy, we performed exome sequencing in a large cohort of 528 children with cardiomyopathy. Using clinical interpretation guidelines and targeting genes implicated in cardiomyopathy, we identified a genetic cause in 32% of affected individuals. Cardiomyopathy sub-phenotypes differed by ancestry, age at diagnosis, and family history. Infants < 1 year were less likely to have a molecular diagnosis (p < 0.001). Using a discovery set of 1,703 candidate genes and informatic tools, we identified rare and damaging variants in 56% of affected individuals. We see an excess burden of damaging variants in affected individuals as compared to two independent control sets, 1000 Genomes Project (p < 0.001) and SPARK parental controls (p < 1 × 10-16). Cardiomyopathy variant burden remained enriched when stratified by ancestry, variant type, and sub-phenotype, emphasizing the importance of understanding the contribution of these factors to genetic architecture. Enrichment in this discovery candidate gene set suggests multigenic mechanisms underlie sub-phenotype-specific causes and presentations of cardiomyopathy. These results identify important information about the genetic architecture of pediatric cardiomyopathy and support recommendations for clinical genetic testing in children while illustrating differences in genetic architecture by age, ancestry, and sub-phenotype and providing rationale for larger studies to investigate multigenic contributions.
Assuntos
Cardiomiopatia Dilatada/genética , Exoma , Regulação da Expressão Gênica , Genótipo , Padrões de Herança , Idade de Início , Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Dilatada/patologia , Estudos de Casos e Controles , Criança , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Testes Genéticos , Variação Genética , Humanos , Masculino , Fenótipo , Guias de Prática Clínica como Assunto , Sequenciamento do ExomaRESUMO
Unnatural amino acids are key building blocks in therapeutically relevant peptides. Thus, the development of novel methods to increase the structural diversity of the unnatural amino acid pool is needed. Herein, a photoredox-mediated decarboxylative radical conjugate addition to dehydroalanine derivatives is disclosed. Mild, robust, and general conditions were identified and applied to the diastereoselective synthesis of unnatural amino acids and the late-stage derivatization of a tripeptide.
Assuntos
Aminoácidos , Peptídeos , Aminas , Aminoácidos/química , Oxirredução , Peptídeos/químicaRESUMO
Restrictive cardiomyopathy (RCM) is a rare and distinct form of cardiomyopathy characterized by normal ventricular chamber dimensions, normal myocardial wall thickness, and preserved systolic function. The abnormal myocardium, however, demonstrates impaired relaxation. To date, dominant variants causing RCM have been reported in a small number of sarcomeric or cytoskeletal genes, but the genetic causes in a majority of cases remain unexplained, especially in early childhood. Here, we describe two RCM families with childhood onset: one in a large family with a history of autosomal dominant RCM and the other a family with affected monozygotic, dichorionic/diamniotic twins. Exome sequencing found a pathogenic filamin C (FLNC) variant in each: p.Pro2298Leu, which segregates with disease in the large autosomal dominant RCM family, and p.Tyr2563Cys in both affected twins. In vitro expression of both mutant proteins yielded aggregates of FLNC containing actin in C2C12 myoblast cells. Recently, a number of variants in FLNC have been described that cause hypertrophic, dilated, and restrictive cardiomyopathies. Our data presented here provide further evidence for the role of FLNC in pediatric RCM, and suggest the need to include FLNC in genetic testing of cardiomyopathy patients including those with early ages of onset.
Assuntos
Cardiomiopatia Restritiva/genética , Sequenciamento do Exoma/métodos , Filaminas/genética , Filaminas/metabolismo , Mutação , Idade de Início , Animais , Células Cultivadas , Criança , Pré-Escolar , Feminino , Filaminas/química , Testes Genéticos , Humanos , Lactente , Masculino , Modelos Moleculares , Linhagem , RatosRESUMO
Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results.
Assuntos
Aneurisma da Aorta Torácica/genética , Proteínas de Ligação ao Cálcio/genética , Proteínas Contráteis/genética , Glicoproteínas/genética , Síndrome de Loeys-Dietz/genética , Síndrome de Marfan/genética , Quinase de Cadeia Leve de Miosina/genética , Proteína Smad3/genética , Fator de Crescimento Transformador beta2/genética , Adolescente , Adulto , Idoso , Aneurisma da Aorta Torácica/fisiopatologia , Criança , Exoma/genética , Feminino , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome de Loeys-Dietz/patologia , Masculino , Síndrome de Marfan/patologia , Pessoa de Meia-Idade , Mutação , LinhagemRESUMO
A series of N-heterocyclic pyridinone catechol-O-methyltransferase (COMT) inhibitors were synthesized. Physicochemical properties, including ligand lipophilic efficiency (LLE) and clogP, were used to guide compound design and attempt to improve inhibitor pharmacokinetics. Incorporation of heterocyclic central rings provided improvements in physicochemical parameters but did not significantly reduce in vitro or in vivo clearance. Nevertheless, compound 11 was identified as a potent inhibitor with sufficient in vivo exposure to significantly affect the dopamine metabolites homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC), and indicate central COMT inhibition.
Assuntos
Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Compostos Heterocíclicos/farmacologia , Piridonas/farmacologia , Animais , Inibidores de Catecol O-Metiltransferase/síntese química , Inibidores de Catecol O-Metiltransferase/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Piridonas/síntese química , Piridonas/química , Ratos , Relação Estrutura-AtividadeRESUMO
Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Nav1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.
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Inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous disorders that account for â¼30% of pediatric cases of bone marrow failure and are often associated with developmental abnormalities and cancer predisposition. This article reports the laboratory validation and clinical utility of a large-scale, custom-designed next-generation sequencing panel, Children's Hospital of Philadelphia (CHOP) IBMFS panel, for the diagnosis of IBMFS in a cohort of pediatric patients. This panel demonstrated excellent analytic accuracy, with 100% sensitivity, ≥99.99% specificity, and 100% reproducibility on validation samples. In 269 patients with suspected IBMFS, this next-generation sequencing panel was used for identifying single-nucleotide variants, small insertions/deletions, and copy number variations in mosaic or nonmosaic status. Sixty-one pathogenic/likely pathogenic variants (54 single-nucleotide variants/insertions/deletions and 7 copy number variations) and 24 hypomorphic variants were identified, resulting in the molecular diagnosis of IBMFS in 21 cases (7.8%) and exclusion of IBMFS with a diagnosis of a blood disorder in 10 cases (3.7%). Secondary findings, including evidence of early hematologic malignancies and other hereditary cancer-predisposition syndromes, were observed in 9 cases (3.3%). The CHOP IBMFS panel was highly sensitive and specific, with a significant increase in the diagnostic yield of IBMFS. These findings suggest that next-generation sequencing-based panel testing should be a part of routine diagnostics in patients with suspected IBMFS.
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Anemia Aplástica , Doenças da Medula Óssea , Hemoglobinúria Paroxística , Humanos , Criança , Anemia Aplástica/diagnóstico , Anemia Aplástica/genética , Doenças da Medula Óssea/diagnóstico , Doenças da Medula Óssea/genética , Síndrome Congênita de Insuficiência da Medula Óssea , Variações do Número de Cópias de DNA/genética , Reprodutibilidade dos Testes , Hemoglobinúria Paroxística/diagnóstico , Hemoglobinúria Paroxística/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , NucleotídeosRESUMO
Herpesvirus infections are ubiquitous, with over 95% of the adult population infected by at least one strain. While most of these infections resolve without treatment in healthy individuals, they can cause significant morbidity and mortality in immunocompromised, stem cell, or organ transplant patients. Current nucleoside standards of care provide meaningful benefit but are limited due to poor tolerability, resistance, and generally narrow spectrum of activity. Herpesviruses share a conserved DNA polymerase, the inhibition of which is validated as an effective strategy to disrupt viral replication. By utilizing a non-nucleoside inhibitor of the viral DNA polymerase, we sought to develop agents covering multiple herpesviruses (e.g., CMV, VZV, HSV1/2, EBV, and HHV6). Herein is described the invention of an oxazolidinone class of broad-spectrum non-nucleoside herpes antiviral inhibitors. A lead compound (42) with potent biochemical and broad-spectrum cellular activity was found to be efficacious in murine models against both HSV-1 and CMV infection.
RESUMO
Because the clinical impact of cancer genomics is being increasingly recognized, tumor sequencing will likely continue to expand in breadth and scope. Therefore, it is vital for laboratory professionals to adopt the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists guidelines and create a standardized system of classification and nomenclature for somatic variants. Combining robust bioinformatics pipelines with thorough data analysis is necessary to efficiently and reproducibly identify and assess the impact of clinically relevant variants.
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Testes Genéticos , Neoplasias , Biologia Computacional , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Patologia MolecularRESUMO
CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of "CIC-rearranged" sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.
Assuntos
Sarcoma de Células Pequenas , Sarcoma , Neoplasias de Tecidos Moles , Ataxina-1/genética , Biomarcadores Tumorais/genética , Expressão Gênica , Humanos , Lactente , Metilação , Proteínas de Fusão Oncogênica/genética , Proteínas Repressoras/genética , Estudos Retrospectivos , Sarcoma/genética , Sarcoma/patologia , Sarcoma de Células Pequenas/diagnóstico , Sarcoma de Células Pequenas/genética , Sarcoma de Células Pequenas/patologia , Neoplasias de Tecidos Moles/genética , Fatores de Transcrição/genéticaRESUMO
Li-Fraumeni syndrome (LFS) is one of the most common cancer predisposition syndromes that affects both children and adults. Individuals with LFS are at an increased risk of developing various types of cancer over their lifetime including soft tissue sarcomas, osteosarcomas, breast cancer, leukemia, brain tumors, and adrenocortical carcinoma. Heterozygous germline pathogenic variants in the tumor suppressor gene TP53 are the known causal genetic defect for LFS. Single-nucleotide variants (SNVs) including missense substitutions that occur in the highly conserved DNA binding domain of the protein are the most common alterations, followed by nonsense and splice site variants. Gross copy-number changes in TP53 are rare and account for <1% of all variants. Using next-generation sequencing (NGS) panels, we identified a paternally inherited germline intragenic duplication of TP53 in a child with metastatic osteosarcoma who later developed acute myeloid leukemia (AML). Transcriptome sequencing (RNA-seq) demonstrated the duplication was tandem, encompassing exons 2-6 and 28 nt of the untranslated region (UTR) upstream of the start codon in exon 2. The inclusion of the 28 nt is expected to result in a frameshift with a stop codon 18 codons downstream from the exon 6, leading to a loss-of-function allele. This case highlights the significance of simultaneous identification of both significant copy-number variants as well as SNVs/indels using NGS panels.
Assuntos
Neoplasias do Córtex Suprarrenal , Neoplasias da Mama , Síndrome de Li-Fraumeni , Proteína Supressora de Tumor p53 , Adulto , Neoplasias da Mama/genética , Criança , Feminino , Duplicação Gênica/genética , Predisposição Genética para Doença , Mutação em Linhagem Germinativa/genética , Humanos , Síndrome de Li-Fraumeni/genética , Proteína Supressora de Tumor p53/genéticaRESUMO
The rapid development of next-generation sequencing (NGS) technology, including advances in sequencing chemistry, sequencing technologies, bioinformatics, and data interpretation, has facilitated its wide clinical application in precision medicine. This review describes current sequencing technologies, including short- and long-read sequencing technologies, and highlights the clinical application of NGS in inherited diseases, oncology, and infectious diseases. We review NGS approaches and clinical diagnosis for constitutional disorders; summarize the application of U.S. Food and Drug Administration-approved NGS panels, cancer biomarkers, minimal residual disease, and liquid biopsy in clinical oncology; and consider epidemiological surveillance, identification of pathogens, and the importance of host microbiome in infectious diseases. Finally, we discuss the challenges and future perspectives of clinical NGS tests.
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Biologia Computacional/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Medicina de Precisão , Biomarcadores Tumorais/genética , Doenças Transmissíveis/diagnóstico , Doenças Transmissíveis/genética , Variações do Número de Cópias de DNA/genética , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNARESUMO
Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.
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Cardiomiopatias/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Sistema de Registros , Adolescente , Cardiomiopatias/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Morbidade/tendências , Estudos Retrospectivos , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologia , Sequenciamento do Exoma/métodosRESUMO
PALB2 (partner and localizer of BRCA2) gene encodes a protein that colocalizes with BRCA2 in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2PALB2 plays a critical role in maintaining genome integrity through its role in the Fanconi anemia and homologous recombination DNA repair pathways. It has a known loss-of-function disease mechanism. Biallelic PALB2 pathogenic variants have been described in autosomal recessive Fanconi anemia. Heterozygous pathogenic variants in PALB2 are associated with increased risk for female and male breast cancer and pancreatic cancer (Science 324: 217; Cancer Res 71: 2222-2229; N Engl J Med 371: 497-506). Heterozygous germline PALB2 mutations have also been observed in patients with medulloblastoma (Lancet Oncol 19: 785-798). However, PALB2-related cancer predisposition to high-grade gliomas has not been reported. Here we report a germline PALB2 pathogenic variant (c.509_510delGA, p.Arg170Ilefs*14, NM_024675.3) found in a pediatric patient with high-grade glioma. This variant was first identified by tumor sequencing using the Children's Hospital of Philadelphia (CHOP) Comprehensive Solid Tumor Panel and then confirmed to be a germline change using the CHOP Comprehensive Hereditary Cancer Panel on DNA from a blood sample of this patient. Parental studies showed that this variant was paternally inherited. Further studies are needed to illustrate if pathogenic variants in PALB2 convey increased risk to developing brain tumor. This case also highlights the potential of identifying germline mutation through tumor sequencing.
Assuntos
Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Glioma/genética , Criança , Proteína do Grupo de Complementação N da Anemia de Fanconi/metabolismo , Feminino , Predisposição Genética para Doença , Células Germinativas/metabolismo , Mutação em Linhagem Germinativa/genética , HumanosRESUMO
The measurement of receptor occupancy (RO) using positron emission tomography (PET) has been instrumental in guiding discovery and development of CNS directed therapeutics. We and others have investigated muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs) for the treatment of symptoms associated with neuropsychiatric disorders. In this article, we describe the synthesis, in vitro, and in vivo characterization of a series of central pyridine-related M4 PAMs that can be conveniently radiolabeled with carbon-11 as PET tracers for the in vivo imaging of an allosteric binding site of the M4 receptor. We first demonstrated its feasibility by mapping the receptor distribution in mouse brain and confirming that a lead molecule 1 binds selectively to the receptor only in the presence of the orthosteric agonist carbachol. Through a competitive binding affinity assay and a number of physiochemical properties filters, several related compounds were identified as candidates for in vivo evaluation. These candidates were then radiolabeled with 11C and studied in vivo in rhesus monkeys. This research eventually led to the discovery of the clinical radiotracer candidate [11C]MK-6884.
Assuntos
Regulação Alostérica/efeitos dos fármacos , Agonistas Muscarínicos/farmacologia , Piridinas/farmacologia , Receptor Muscarínico M4/agonistas , Animais , Células CHO , Radioisótopos de Carbono/química , Radioisótopos de Carbono/farmacologia , Cricetulus , Humanos , Macaca mulatta , Agonistas Muscarínicos/química , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/metabolismo , Tomografia por Emissão de Pósitrons , Piridinas/química , Receptor Muscarínico M4/metabolismoRESUMO
X-ray inspection systems are critical in medical, non-destructive testing, and security applications, with systems typically measuring attenuation along straight-line paths connecting sources and detectors. Computed tomography (CT) systems can provide higher-quality images than single- or dual-view systems, but the need to measure many projections leads to greater system cost and complexity. Typically, off-angle Compton scattered photons are treated as noise during tomographic inversion. We seek to maximize the image quality of limited-view systems by combining attenuation data with measurements of Compton-scattered photons, exploiting the fact that the broken-ray paths followed by scattered photons provide additional geometric sampling of the scene. We describe a single-scatter forward model for Compton-scatter data measured with energy-resolving detectors, and demonstrate a reconstruction algorithm for density that combines both attenuation and scatter measurements. The experimental results suggest that including Compton-scattered data in the reconstruction process can improve image quality for density reconstruction using limited-view systems.
RESUMO
Herein we describe the discovery and optimization of a new series of 2,3-disubstituted and 2,3,6-trisubstituted muscarinic acetylcholine receptorâ 4 (M4 ) positive allosteric modulators (PAMs). Iterative libraries enabled rapid exploration of one-dimensional structure-activity relationships (SAR) and identification of potency-enhancing heterocycle and N-alkyl pyrazole substituents. Further optimization led to identification of the potent, receptor-subtype-selective, brain-penetrant tool compound 24 (7-[3-[1-[(1-fluorocyclopentyl)methyl]pyrazol-4-yl]-6-methyl-2-pyridyl]-3-methoxycinnoline). It is efficacious in preclinical assays that are predictive of antipsychotic effects, producing dose-dependent reversal of amphetamine-induced hyperlocomotion in rats and mice, but not in M4 knockout mice. Cholinergic-related adverse effects observed in rats treated with 24 at unbound plasma concentrations more than 3-fold higher than an efficacious dose in the hyperlocomotion assay were fewer and less severe than those observed in rats treated with the nonselective M4 agonist xanomeline, suggesting a receptor-subtype-selective PAM has the potential for an improved safety profile.
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Descoberta de Drogas , Piridinas/química , Piridinas/farmacologia , Receptor Muscarínico M4/efeitos dos fármacos , Regulação Alostérica , Animais , Humanos , Ratos , Receptor Muscarínico M4/metabolismo , Relação Estrutura-AtividadeRESUMO
Isotopic perturbation of degenerate equilibrium is used to determine whether tetramethylethylenechloronium and tetramethylethylenebromonium ions are closed 1,2-bridged structures or rapid equilibria of open beta-halocarbenium ions. The observed 13C NMR isotope shifts are consistent with a combination of large equilibrium shifts and small upfield intrinsic shifts. The presence of equilibrium shifts in both halonium ions indicates that these ions are not closed 1,2-bridged structures. Rather, they are best represented by equilibria of beta-halocarbenium ions.
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Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies.