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  • 1
    Language: English
    In: Orphanet journal of rare diseases, 2012-09-18, Vol.7 (1), p.68-68
    Description: Systemic primary carnitine deficiency (CDSP) is an autosomal recessive disorder of carnitine transportation. The clinical manifestations of CDSP can vary widely with respect to age of onset, organ involvement, and severity of symptoms, but are typically characterized by episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia in infants; skeletal myopathy, elevated creatine kinase (CK), and cardiomyopathy in childhood; or cardiomyopathy, arrhythmias, or fatigability in adulthood. The diagnosis can be suspected on newborn screening, but is established by demonstration of low plasma free carnitine concentration (〈5 μM, normal 25-50 μM), reduced fibroblast carnitine transport (〈10% of controls), and molecular testing of the SLC22A5 gene. The incidence of CDSP varies depending on ethnicity; however the frequency in the United States is estimated to be approximately 1 in 50,000 individuals based on newborn screening data. CDSP is caused by recessive mutations in the SLC22A5 gene. This gene encodes organic cation transporter type 2 (OCTN2) which transport carnitine across cell membranes. Over 100 mutations have been reported in this gene with the c.136C 〉 T (p.P46S) mutation being the most frequent mutation identified. CDSP should be differentiated from secondary causes of carnitine deficiency such as various organic acidemias and fatty acid oxidation defects. CDSP is an autosomal recessive condition; therefore the recurrence risk in each pregnancy is 25%. Carrier screening for at-risk individuals and family members should be obtained by performing targeted mutation analysis of the SLC22A5 gene since plasma carnitine analysis is not a sufficient methodology for determining carrier status. Antenatal diagnosis for pregnancies at increased risk of CDSP is possible by molecular genetic testing of extracted DNA from chorionic villus sampling or amniocentesis if both mutations in SLC22A5 gene are known. Once the diagnosis of CDSP is established in an individual, an echocardiogram, electrocardiogram, CK concentration, liver transaminanses measurement, and pre-prandial blood sugar levels, should be performed for baseline assessment. Primary treatment involves supplementation of oral levocarnitine (L-carnitine) at a dose of 50-400 mg/kg/day divided into three doses. No formal surveillance guidelines for individuals with CDSP have been established to date, however the following screening recommendations are suggested: annual echocardiogram and electrocardiogram, frequent plasma carnitine levels, and CK and liver transaminases measurement can be considered during acute illness. Adult women with CDSP who are planning to or are pregnant should meet with a metabolic or genetic specialist ideally before conception to discuss management of carnitine levels during pregnancy since carnitine levels are typically lower during pregnancy. The prognosis for individuals with CDSP depends on the age, presentation, and severity of symptoms at the time of diagnosis; however the long-term prognosis is favorable as long as individuals remain on carnitine supplementation.
    Subject(s): Adult ; Age ; Arrhythmia ; Blood sugar ; Carnitine - deficiency ; Child ; Creatine ; Creatine kinase ; Diagnosis, Differential ; Fatty acids ; Fetuses ; Genetic Counseling ; Genetic screening ; Humans ; Hypoglycemia ; Levocarnitine ; Liver ; Medical screening ; Metabolism, Inborn Errors - diagnosis ; Metabolism, Inborn Errors - pathology ; Metabolism, Inborn Errors - therapy ; Metabolism, Inborn errors of ; Musculoskeletal system ; Newborn babies ; Plasma ; Pregnancy ; Pregnant women ; Presentations ; Prognosis ; Review ; Womens health
    ISSN: 1750-1172
    E-ISSN: 1750-1172
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 2
    Language: English
    In: American journal of human genetics, 2015-11-05, Vol.97 (5), p.691-707
    Description: The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.
    Subject(s): Abnormalities, Multiple - genetics ; Abnormalities, Multiple - pathology ; Charcot-Marie-Tooth Disease - genetics ; Charcot-Marie-Tooth Disease - pathology ; Child ; Child, Preschool ; Chromosome Disorders - genetics ; Chromosome Disorders - pathology ; Chromosome Duplication - genetics ; Chromosomes, Human, Pair 17 - genetics ; Comparative Genomic Hybridization ; Development and progression ; DNA replication ; Female ; Follow-Up Studies ; Gene Duplication ; Gene Rearrangement ; Genetic disorders ; Genome, Human ; Genomics ; Genomics - methods ; Genotype & phenotype ; Health aspects ; Humans ; Infant ; Male ; Models, Genetic ; Myelin Proteins - genetics ; Phenotype ; Prognosis ; Recombination, Genetic ; Transcription Factors - genetics
    ISSN: 0002-9297
    E-ISSN: 1537-6605
    Source: PubMed Central
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  • 3
    Article
    Article
    2012
    ISSN: 1750-1172 
    Language: English
    In: Orphanet journal of rare diseases, 2012-01-04, Vol.7 (1), p.2-2
    Description: Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals. DISEASE NAME AND SYNONYMS: Chromosome 15q24 deletion syndrome. 15q24 deletion syndrome. 15q24 microdeletion syndrome.
    Subject(s): Care and treatment ; Chromosome Aberrations ; Chromosome abnormalities ; Chromosomes, Human, Pair 15 ; Developmental Disabilities - genetics ; Diagnosis ; Humans ; Prognosis ; Review ; Risk factors
    ISSN: 1750-1172
    E-ISSN: 1750-1172
    Source: BioMedCentral Open Access
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: DOAJ Directory of Open Access Journals - Not for CDI Discovery
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  • 4
    Language: English
    In: American journal of medical genetics. Part C, Seminars in medical genetics, 2018-03, Vol.178 (1), p.5-9
    Description: By enabling precise genetic diagnosis and treatment there is great potential for inexpensive, accurate, and widely accessible genomic information to transform health care and improve the general well‐being of virtually every person. To maximize this potential, approaches to genetic counseling and the role of genetic counselors will need to adapt to fit changing clinical and commercial needs worldwide. This will require overcoming multiple challenges including an inadequate workforce; development and implementation of alternate models of service delivery; integration of new technologies to improve, extend, and expand services; and support for equitable education and counseling among all populations. Genetic counselors are aptly poised to take on these challenges. The result will be better informed patients and families more capable of utilizing genetic information appropriately, making autonomous decisions about their care, and modifying their approach to disease risk to actively contribute to their health. The contributors to this issue of Seminars discuss how key areas of genetic counseling need to evolve and how genetic counselors can play a role in shaping the future of precision health.
    Subject(s): Analysis ; Biological evolution ; Genetic counseling ; Genetic counselling ; Genetic research ; Genetic screening ; Genetic testing ; Health care ; Health care reform ; Health risks ; Information processing ; Medical genetics ; New technology ; Occupational health ; Population genetics
    ISSN: 1552-4868
    E-ISSN: 1552-4876
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 5
    Language: English
    In: American journal of medical genetics. Part A, 2019-07, Vol.179 (7), p.1376-1382
    Description: The myelin regulatory factor gene (MYRF) encodes a transcription factor that is widely expressed. There is increasing evidence that heterozygous loss‐of‐function variants in MYRF can lead to abnormal development of the heart, genitourinary tract, diaphragm, and lungs. Here, we searched a clinical database containing the results of 12,000 exome sequencing studies. We identified three previously unreported males with putatively deleterious variants in MYRF: one with a point mutation predicted to affect splicing and two with frameshift variants. In all cases where parental DNA was available, these variants were found to have arisen de novo. The phenotypes identified in these subjects included a variety of congenital heart defects (CHD) (hypoplastic left heart syndrome, scimitar syndrome, septal defects, and valvular anomalies), genitourinary anomalies (ambiguous genitalia, hypospadias, and cryptorchidism), congenital diaphragmatic hernia, and pulmonary hypoplasia. The phenotypes seen in our subjects overlap those described in individuals diagnosed with PAGOD syndrome [MIM# 202660], a clinically defined syndrome characterized by pulmonary artery and lung hypoplasia, agonadism, omphalocele, and diaphragmatic defects that can also be associated with hypoplastic left heart and scimitar syndrome. These cases provide additional evidence that haploinsufficiency of MYRF causes a genetic syndrome whose cardinal features include CHD, urogenital anomalies, congenital diaphragmatic hernia, and pulmonary hypoplasia. We also conclude that consideration should be given to screening individuals with PAGOD for pathogenic variants in MYRF, and that individuals with MYRF deficiency who survive the neonatal period should be monitored closely for developmental delay and intellectual disability.
    Subject(s): congenital diaphragmatic hernia ; congenital heart defects ; Congenital heart disease ; Coronary heart disease ; Cryptorchidism ; Defects ; Diaphragm ; Genetic disorders ; Genetics & Heredity ; Genitalia ; Genitourinary tract ; Haploinsufficiency ; Heart ; Hernia ; Hernias ; Hypoplasia ; Life Sciences & Biomedicine ; Lungs ; Myelin ; Myelin regulatory factor ; MYRF ; Neonates ; PAGOD syndrome ; Phenotypes ; Point mutation ; Pulmonary arteries ; Pulmonary artery ; pulmonary hypoplasia ; Science & Technology ; Splicing ; urogenital anomalies
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Wiley Online Library All Journals
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  • 6
    Language: English
    In: Prenatal diagnosis, 2020-09, Vol.40 (10), p.1246-1257
    Description: 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): Algorithms ; Design criteria ; Disease ; Gene mapping ; Genes ; Genetic counseling ; Genetic counselling ; Genetic screening ; Mapping
    ISSN: 0197-3851
    E-ISSN: 1097-0223
    Source: Hellenic Academic Libraries Link
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  • 7
    Language: English
    In: Blood, 2018-08-09, Vol.132 (6), p.658-662
    Description: Publisher's Note: There is a Blood Commentary on this article in this issue.
    Subject(s): Abnormalities, Multiple - genetics ; Abridged Index Medicus ; Bone Marrow Transplantation ; Child ; Consanguinity ; Fatal Outcome ; Female ; Gonadal Dysgenesis, 46,XY - genetics ; Hematopoietic Stem Cell Transplantation ; Humans ; Infant ; Intellectual Disability - genetics ; Letter to ; Male ; Pedigree ; Phenotype ; Primary Myelofibrosis - congenital ; Primary Myelofibrosis - genetics ; Primary Myelofibrosis - therapy ; Syndrome ; Vesicular Transport Proteins - deficiency ; Vesicular Transport Proteins - genetics ; Vesicular Transport Proteins - physiology
    ISSN: 0006-4971
    E-ISSN: 1528-0020
    Source: Alma/SFX Local Collection
    Source: American Society of Hematology
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  • 8
    Language: English
    In: American journal of medical genetics. Part A, 2022-06, Vol.188 (6), p.1915-1927
    Description: RASopathies are a group of genetic disorders that are caused by genes that affect the canonical Ras/mitogen‐activated protein kinase (MAPK) signaling pathway. Despite tremendous progress in understanding the molecular consequences of these genetic anomalies, little movement has been made in translating these findings to the clinic. This year, the seventh International RASopathies Symposium focused on expanding the research knowledge that we have gained over the years to enhance new discoveries in the field, ones that we hope can lead to effective therapeutic treatments. Indeed, for the first time, research efforts are finally being translated to the clinic, with compassionate use of Ras/MAPK pathway inhibitors for the treatment of RASopathies. This biannual meeting, organized by the RASopathies Network, brought together basic scientists, clinicians, clinician scientists, patients, advocates, and their families, as well as representatives from pharmaceutical companies and the National Institutes of Health. A history of RASopathy gene discovery, identification of new disease genes, and the latest research, both at the bench and in the clinic, were discussed.
    Subject(s): Biological products ; cardiofaciocutaneus syndrome ; Conferences and conventions ; Conferences, meetings and seminars ; Costello syndrome ; Genetic disorders ; Genetic research ; Health aspects ; Kinases ; MAP kinase ; Medical research ; Medicine, Experimental ; neurofibromatosis ; Noonan syndrome ; Pharmaceutical industry ; Protein kinase ; Ras protein ; RASopathy ; Signal transduction ; signaling
    ISSN: 1552-4825
    E-ISSN: 1552-4833
    Source: Hellenic Academic Libraries Link
    Source: Wiley Online Library All Journals
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  • 9
    Language: English
    In: Journal of genetic counseling, 2021-08, Vol.30 (4), p.1181-1190
    Description: Rapid genomic testing is increasingly used in inpatient settings for diagnostic and treatment purposes. With the expansion of genetic testing in this setting, requests for inpatient genetics consultations have increased. There have been reports of genetic counselors working in inpatient care, though their specific roles are not well described. In this study, we characterized the roles of genetic counselors practicing in inpatient care settings in the United States and Canada. Genetic counselors were recruited via professional organization listservs to complete an online survey. The survey gathered information on participants' roles and workflow of inpatient genetics consultation services at their institution. Responses from 132 participants demonstrate that 50.4% of genetic counselors cover genetics consultations as needed or on a rotating schedule (34.6%). They practice in general pediatric (59.1%), neonatal (42.5%), cancer (28.3%), and/or prenatal (18.9%) specialties, among others. Participants reported working independently (16.1%) or with other providers (54.8%), including geneticists and other attending physicians. The workflow of genetics consultation services varies between institutions in the delivery of consults, members of the inpatient genetics consultation care team, and administrative support. Fifty percent of participants reported having no exposure to inpatients during graduate training, and 87.3% of participants reported receiving no institutional training for their inpatient role. This is the first study to describe roles of genetic counselors in inpatient care. It establishes a foundation for future research on inpatient genetic counseling and genetic counseling outcomes in inpatient services. As demand for genetics expertise in inpatient care grows, genetic counselors can be hired to serve inpatient populations alongside genetics and non‐genetics providers.
    Subject(s): Antenatal ; Cancer ; Consultation ; Counselling services ; Counselors ; Genetic counseling ; Genetic counselling ; genetic counselors ; Genetic screening ; Genetic testing ; Genetics ; genetics services ; Inpatient care ; inpatient genetics ; Listservs ; Neonates ; Pediatrics ; Polls & surveys ; Population genetics ; professional development ; Teams ; workforce
    ISSN: 1059-7700
    E-ISSN: 1573-3599
    Source: Wiley Online Library All Journals
    Source: Get It Now
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  • 10
    Language: English
    In: Human molecular genetics, 2017-12-15, Vol.26 (24), p.4937-4950
    Description: Iron-sulfur (Fe-S) clusters are ubiquitous cofactors essential to various cellular processes, including mitochondrial respiration, DNA repair, and iron homeostasis. A steadily increasing number of disorders are being associated with disrupted biogenesis of Fe-S clusters. Here, we conducted whole-exome sequencing of patients with optic atrophy and other neurological signs of mitochondriopathy and identified 17 individuals from 13 unrelated families with recessive mutations in FDXR, encoding the mitochondrial membrane-associated flavoprotein ferrodoxin reductase required for electron transport from NADPH to cytochrome P450. In vitro enzymatic assays in patient fibroblast cells showed deficient ferredoxin NADP reductase activity and mitochondrial dysfunction evidenced by low oxygen consumption rates (OCRs), complex activities, ATP production and increased reactive oxygen species (ROS). Such defects were rescued by overexpression of wild-type FDXR. Moreover, we found that mice carrying a spontaneous mutation allelic to the most common mutation found in patients displayed progressive gait abnormalities and vision loss, in addition to biochemical defects consistent with the major clinical features of the disease. Taken together, these data provide the first demonstration that germline, hypomorphic mutations in FDXR cause a novel mitochondriopathy and optic atrophy in humans.
    ISSN: 0964-6906
    E-ISSN: 1460-2083
    Source: Alma/SFX Local Collection
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