Subject(s)
Delivery of Health Care , Humans , Health Equity , Healthcare Disparities , COVID-19/epidemiologyABSTRACT
Melanoma is the most deadly form of skin cancer and DiGeorge syndrome (DGS) is the most frequent interstitial deletion syndrome. We characterized a novel balanced t(9;22)(p21;q11.2) translocation in a patient with melanoma, DNA repair deficiency, and features of DGS including deafness and malformed inner ears. Using chromosome sorting, we located the 9p21 breakpoint in CDKN2A intron 1. This resulted in underexpression of the tumor suppressor p14 alternate reading frame (p14ARF); the reduced DNA repair was corrected by transfection with p14ARF. Ultraviolet radiation-type p14ARF mutations in his melanoma implicated p14ARF in its pathogenesis. The 22q11.2 breakpoint was located in a palindromic AT-rich repeat (PATRR22). We identified a new gene, FAM230A, that contains PATRR22 within an intron. The 22q11.2 breakpoint was located 800 kb centromeric to TBX1, which is required for inner ear development. TBX1 expression was greatly reduced. The translocation resulted in a chimeric transcript encoding portions of p14ARF and FAM230A. Inhibition of chimeric p14ARF-FAM230A expression increased p14ARF and TBX1 expression and improved DNA repair. Expression of the chimera in normal cells produced dominant negative inhibition of p14ARF. Similar chimeric mRNAs may mediate haploinsufficiency in DGS or dominant negative inhibition of other genes such as those involved in melanoma.
Subject(s)
DNA Repair-Deficiency Disorders/genetics , Deafness/genetics , Gene Fusion , Melanoma/genetics , T-Box Domain Proteins/genetics , Translocation, Genetic , Tumor Suppressor Protein p14ARF/genetics , Base Sequence , Carrier Proteins , Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 9 , DNA Repair-Deficiency Disorders/metabolism , Deafness/metabolism , Genes, p16 , Humans , Male , Melanoma/metabolism , Molecular Sequence Data , RNA, Long Noncoding , Sequence Analysis, DNA , T-Box Domain Proteins/metabolism , Tumor Suppressor Protein p14ARF/metabolism , Young AdultABSTRACT
Advances in technology have accelerated the translation of genetics and genomics into the arena of cancer prevention. This provides unique opportunities to individualize cancer risk prediction so early intervention can either modify risk or allow for early diagnosis thereby potentially decreasing the morbidity and mortality of cancer and containing costs. While the full potential of these genetic/genomic discoveries have yet to be realized, many have clear clinical relevance such as the value of family history and/or tumor profiling to identify those who may harbor a mutation in a cancer susceptibility gene and are therefore candidates for genetic testing. Here, we provide an overview of the scope of genetic and genomic influences on cancer risk assessment and the entire spectrum of cancer prevention.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Neoplasm Proteins/genetics , Neoplasms/genetics , Neoplasms/prevention & control , Pharmacogenetics , Humans , Neoplasms/pathologyABSTRACT
To complement the 2005 Annual Clinical Focus on medical genomics, AFP is publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. This review discusses Klinefelter syndrome.
Subject(s)
Klinefelter Syndrome/diagnosis , Humans , Klinefelter Syndrome/drug therapy , Klinefelter Syndrome/genetics , MaleABSTRACT
To complement the 2005 Annual Clinical Focus on medical genomics, AFP is publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the type of care they might require in the future. This review discusses Prader-Willi syndrome.
Subject(s)
Prader-Willi Syndrome/diagnosis , Child , Chromosomes, Human, Pair 15/genetics , Humans , Prader-Willi Syndrome/epidemiology , Prader-Willi Syndrome/genetics , Prader-Willi Syndrome/therapyABSTRACT
The collection of a family history ranges from simply asking patients if family members have the same presenting illness to diagramming complex medical and psychosocial relationships as part of a family genogram. The three-generation pedigree provides a pictorial representation of diseases within a family and is the most efficient way to assess hereditary influences on disease. Two recent events have made family history assessment more important than ever: the completion of the Human Genome Project with resultant identification of the inherited causes of many diseases, and the establishment of national clinical practice guidelines based on systematic reviews of preventive interventions. The family history is useful in stratifying a patient's risk for rare single-gene disorders and more common diseases with multiple genetic and environmental contributions. Major organizations have endorsed using standardized symbols in pedigrees to identify inherited contributions to disease.
Subject(s)
Medical History Taking , Pedigree , Genetic Predisposition to Disease , Genetic Testing , HumansABSTRACT
To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The first review in this series discusses fragile X syndrome.
Subject(s)
Fragile X Syndrome/diagnosis , Fragile X Syndrome/therapy , Adult , Age Distribution , Child , Craniofacial Abnormalities/genetics , Developmental Disabilities/genetics , Facial Bones/abnormalities , Family Practice/methods , Female , Fragile X Syndrome/epidemiology , Fragile X Syndrome/genetics , Genetic Carrier Screening , Genetic Counseling , Genetic Testing , Humans , Information Services , Inheritance Patterns/genetics , Internet , Male , Medical History Taking , Middle Aged , Mutation , Patient Care Team/organization & administration , Pedigree , Phenotype , Primary Health Care/methods , Primary Ovarian Insufficiency/geneticsABSTRACT
To complement the 2005 Annual Clinical Focus on medical genomics, AFP will be publishing a series of short reviews on genetic syndromes. This series was designed to increase awareness of these diseases so that family physicians can recognize and diagnose children with these disorders and understand the kind of care they might require in the future. The second review in this series discusses fetal alcohol syndrome and fetal alcohol spectrum disorders.