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1.
Prenat Diagn ; 40(10): 1246-1257, 2020 09.
Article in English | MEDLINE | ID: mdl-32474937

ABSTRACT

BACKGROUND: Disease severity is important when considering genes for inclusion on reproductive expanded carrier screening (ECS) panels. We applied a validated and previously published algorithm that classifies diseases into four severity categories (mild, moderate, severe, and profound) to 176 genes screened by ECS. Disease traits defining severity categories in the algorithm were then mapped to four severity-related ECS panel design criteria cited by the American College of Obstetricians and Gynecologists (ACOG). METHODS: Eight genetic counselors (GCs) and four medical geneticists (MDs) applied the severity algorithm to subsets of 176 genes. MDs and GCs then determined by group consensus how each of these disease traits mapped to ACOG severity criteria, enabling determination of the number of ACOG severity criteria met by each gene. RESULTS: Upon consensus GC and MD application of the severity algorithm, 68 (39%) genes were classified as profound, 71 (40%) as severe, 36 (20%) as moderate, and one (1%) as mild. After mapping of disease traits to ACOG severity criteria, 170 out of 176 genes (96.6%) were found to meet at least one of the four criteria, 129 genes (73.3%) met at least two, 73 genes (41.5%) met at least three, and 17 genes (9.7%) met all four. CONCLUSION: This study classified the severity of a large set of Mendelian genes by collaborative clinical expert application of a trait-based algorithm. Further, it operationalized difficult to interpret ACOG severity criteria via mapping of disease traits, thereby promoting consistency of ACOG criteria interpretation.


Subject(s)
Congenital Abnormalities/classification , Congenital Abnormalities/diagnosis , Genes, Developmental , Genetic Carrier Screening/methods , Genetic Counseling , Adolescent , Algorithms , Child , Child, Preschool , Congenital Abnormalities/genetics , Congenital Abnormalities/pathology , Female , Genes, Developmental/genetics , Genetic Carrier Screening/standards , Genetic Counseling/methods , Genetic Counseling/standards , Genetic Diseases, Inborn/classification , Genetic Diseases, Inborn/diagnosis , Genetic Diseases, Inborn/genetics , Genetic Diseases, Inborn/pathology , Genetic Predisposition to Disease , Humans , Infant , Infant, Newborn , Male , Practice Guidelines as Topic , Pregnancy , Prenatal Diagnosis/methods , Prenatal Diagnosis/standards , Severity of Illness Index , Young Adult
2.
Oral Oncol ; 93: 101-106, 2019 06.
Article in English | MEDLINE | ID: mdl-31109689

ABSTRACT

OBJECTIVES: Radiotherapy (RT) is associated with an increased risk of cardiovascular disease (CVD), but little is known about the mechanism for vascular injury and methods for early detection. MATERIALS AND METHODS: We conducted a prospective, pilot study of carotid artery inflammation using 18F-labeled 2-fluoro-2-deoxy-d-glucose ([18F]FDG) PET/CT imaging pre- and 3 months post-RT in head-and-neck cancer (HNC) patients. [18F]FDG uptake by the carotid arteries was measured by the maximum and mean target to background ratio (TBRMAX, TBRMEAN) and the mean partial volume corrected standardized uptake value (pvcSUVMEAN). RESULTS: Of the 22 patients who completed both pre and post-RT scans, the majority (82%) had stage III or stage IV disease and received concurrent chemotherapy. TBRMAX, TBRMEAN, and pvcSUVMEAN were all significantly higher 3 months after RT versus before RT with mean difference values (95% CI; p-value) of 0.17 (0.1-0.25; 0.0001), 0.19 (0.12-0.25; 0.0001), and 0.31 g/ml (0.12-0.5; 0.002), respectively. Fifteen patients (68%) had HPV-positive tumors, which were associated with lower pre-RT [18F]FDG signal, but a greater increase in TBRMAX (19% vs 5%), TBRMEAN (21% vs 11%) and pvcSUVMEAN (20% increase vs 3% decrease), compared to HPV negativity. CONCLUSION: There is a significant increase in carotid artery inflammation in HNC patients due to CRT that amounts to a degree that has previously been associated with higher risk for future CVD events. The subset of patients with HPV-positive tumors experienced the greatest increases in vascular inflammation due to CRT. Carotid [18F]FDG uptake may be an early biomarker of RT-related vascular injury.


Subject(s)
Arteritis/diagnostic imaging , Carotid Arteries/diagnostic imaging , Chemoradiotherapy/adverse effects , Head and Neck Neoplasms/therapy , Aged , Female , Fluorodeoxyglucose F18/administration & dosage , Head and Neck Neoplasms/diagnostic imaging , Head and Neck Neoplasms/pathology , Humans , Male , Middle Aged , Neoplasm Staging , Pilot Projects , Positron Emission Tomography Computed Tomography , Prospective Studies
3.
Head Neck ; 39(3): 527-532, 2017 03.
Article in English | MEDLINE | ID: mdl-28032680

ABSTRACT

BACKGROUND: The underlying contributors to cardiovascular disease (CVD) in patients with head and neck squamous cell carcinoma (HNSCC) are poorly characterized. METHODS: Patients with HNSCC who underwent definitive or adjuvant (chemo)radiation between 2011 and 2013 were retrospectively reviewed. The 10-year risk estimates for a CVD event were calculated according to the Framingham Risk Score (FRS). RESULTS: One hundred fifteen patients with predominantly stage III/IV HNSCC had a median follow-up of 2 years. At diagnosis, 23% of patients had CVD. The FRS was higher among patients with laryngeal cancer versus other sites (20.5% vs 14.4%). Twenty-four percent of all patients had uncontrolled blood pressure at diagnosis. Among the patients with CVD, 41% were not taking antiplatelet therapy and 30% were not taking statin therapy. Thirty-four percent of patients without CVD had indications for initiating statin therapy. CONCLUSION: Patients with HNSCC have a high baseline CVD risk and many do not receive optimal preventive care. © 2016 Wiley Periodicals, Inc. Head Neck 39: 527-532, 2017.


Subject(s)
Carcinoma, Squamous Cell/radiotherapy , Cardiovascular Diseases/etiology , Cardiovascular Diseases/prevention & control , Head and Neck Neoplasms/radiotherapy , Radiotherapy, Intensity-Modulated/adverse effects , Adult , Age Distribution , Aged , Aged, 80 and over , Carcinoma, Squamous Cell/complications , Carcinoma, Squamous Cell/diagnosis , Cardiovascular Diseases/epidemiology , Chemoradiotherapy/adverse effects , Cohort Studies , Female , Follow-Up Studies , Head and Neck Neoplasms/complications , Head and Neck Neoplasms/diagnosis , Humans , Incidence , Male , Middle Aged , Retrospective Studies , Risk Assessment , Sex Distribution , Squamous Cell Carcinoma of Head and Neck , Time Factors
4.
Eur J Hum Genet ; 23(9): 1165-70, 2015 Sep.
Article in English | MEDLINE | ID: mdl-25424711

ABSTRACT

KAT6B sequence variants have been identified previously in both patients with the Say-Barber-Biesecker type of blepharophimosis mental retardation syndromes (SBBS) and in the more severe genitopatellar syndrome (GPS). We report on the findings in a previously unreported group of 57 individuals with suggestive features of SBBS or GPS. Likely causative variants have been identified in 34/57 patients and were commonly located in the terminal exons of KAT6B. Of those where parental samples could be tested, all occurred de novo. Thirty out of thirty-four had truncating variants, one had a missense variant and the remaining three had the same synonymous change predicted to affect splicing. Variants in GPS tended to occur more proximally to those in SBBS patients, and genotype/phenotype analysis demonstrated significant clinical overlap between SBBS and GPS. The de novo synonymous change seen in three patients with features of SBBS occurred more proximally in exon 16. Statistical analysis of clinical features demonstrated that KAT6B variant-positive patients were more likely to display hypotonia, feeding difficulties, long thumbs/great toes and dental, thyroid and patella abnormalities than KAT6B variant-negative patients. The few reported patients with KAT6B haploinsufficiency had a much milder phenotype, though with some features overlapping those of SBBS. We report the findings in a previously unreported patient with a deletion of the KAT6B gene to further delineate the haploinsufficiency phenotype. The molecular mechanisms giving rise to the SBBS and GPS phenotypes are discussed.


Subject(s)
Blepharophimosis/genetics , Congenital Hypothyroidism/genetics , Craniofacial Abnormalities/genetics , Exons , Heart Defects, Congenital/genetics , Histone Acetyltransferases/genetics , Intellectual Disability/genetics , Joint Instability/genetics , Kidney/abnormalities , Mutation , Patella/abnormalities , Psychomotor Disorders/genetics , Scrotum/abnormalities , Urogenital Abnormalities/genetics , Blepharophimosis/diagnosis , Blepharophimosis/pathology , Child, Preschool , Congenital Hypothyroidism/diagnosis , Congenital Hypothyroidism/pathology , Craniofacial Abnormalities/diagnosis , Craniofacial Abnormalities/pathology , DNA Mutational Analysis , Diagnosis, Differential , Exome , Facies , Female , Gene Expression , Genetic Association Studies , Genotype , Heart Defects, Congenital/diagnosis , Heart Defects, Congenital/pathology , Humans , Intellectual Disability/diagnosis , Intellectual Disability/pathology , Joint Instability/diagnosis , Joint Instability/pathology , Kidney/pathology , Male , Patella/pathology , Phenotype , Psychomotor Disorders/diagnosis , Psychomotor Disorders/pathology , Scrotum/pathology , Severity of Illness Index , Urogenital Abnormalities/diagnosis , Urogenital Abnormalities/pathology
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