Subject(s)
Biomedical Research/organization & administration , Drug-Related Side Effects and Adverse Reactions/genetics , Evidence-Based Medicine/organization & administration , Interdisciplinary Communication , National Institutes of Health (U.S.)/organization & administration , Pharmacogenetics/organization & administration , Pharmacogenomic Variants/genetics , Animals , Biomedical Research/standards , Consensus , Cooperative Behavior , Drug-Related Side Effects and Adverse Reactions/diagnosis , Drug-Related Side Effects and Adverse Reactions/prevention & control , Evidence-Based Medicine/standards , Genotype , Humans , Pharmacogenetics/standards , Phenotype , Practice Guidelines as Topic , Risk Assessment , United StatesABSTRACT
Hospital systems increasingly utilize pharmacogenomic testing to inform clinical prescribing. Successful implementation efforts have been modeled at many academic centers. In contrast, this report provides insights into the formation of a pharmacogenomics consultation service at a safety-net hospital, which predominantly serves low-income, uninsured, and vulnerable populations. The report describes the INdiana GENomics Implementation: an Opportunity for the UnderServed (INGENIOUS) trial and addresses concerns of adjudication, credentialing, and funding.
Subject(s)
Pharmacogenetics/organization & administration , Safety-net Providers/organization & administration , Vulnerable Populations , Academic Medical Centers/organization & administration , Humans , Medically Uninsured , PovertyABSTRACT
This article provides nomenclature recommendations developed by an international workgroup to increase transparency and standardization of pharmacogenetic (PGx) result reporting. Presently, sequence variants identified by PGx tests are described using different nomenclature systems. In addition, PGx analysis may detect different sets of variants for each gene, which can affect interpretation of results. This practice has caused confusion and may thereby impede the adoption of clinical PGx testing. Standardization is critical to move PGx forward.
Subject(s)
Alleles , Genetic Testing/standards , Pharmacogenetics/standards , Terminology as Topic , Genes , Genetic Testing/trends , Genetic Variation , Humans , Pharmacogenetics/trends , Precision MedicineABSTRACT
PURPOSE: We expect that the mutation panel currently recommended for preconception/prenatal CF carrier screening will be modified as new information is learned regarding the phenotype associated with specific mutations and allele frequencies in various populations. One such example is the I148T mutation, originally described as a severe CF mutation. After implementation of CF population-based carrier screening, we learned that I148T exists as a complex allele with 3199del6 in patients with clinical CF, whereas asymptomatic compound heterozygotes for I148T and a second severe CF mutation were negative for 3199del6. METHODS: We performed reflex testing for 3199del6 on 663 unrelated specimens, including I148T heterozygotes, compound heterozygotes, and a homozygous individual. RESULTS: Less than 1% of I148T carriers were also positive for 3199del6. Excluding subjects tested because of a suspected or known CF diagnosis or positive family history, 0.6% of I148T-positive individuals were also positive for 3199del6. We identified 1 I148T homozygote and 6 unrelated compound heterozygous individuals with I148T and a second CF variant (2 of whom also carried 3199del6). In addition, one fetus with echogenic bowel and one infertile male were heterozygous for I148T (3199del6 negative). CONCLUSIONS: Reflex testing for 3199del6 should be considered whenever I148T is identified. Reflex testing is of particular importance for any symptomatic patient or whenever one member of a couple carries a deleterious CF mutation and the other member is an I148T heterozygote. Further population data are required to determine if I148T, in the absence of 3199del6, is associated with mild or atypical CF or male infertility.
Subject(s)
Cystic Fibrosis/genetics , Mutation , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , DNA Mutational Analysis , Female , Gene Frequency , Genotype , Heterozygote , Humans , Male , PhenotypeSubject(s)
Cystic Fibrosis/genetics , Genotype , Humans , Mutation , Polymerase Chain Reaction , Spectrometry, FluorescenceABSTRACT
The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzbacher disease (PMD). Here we describe two new families in which males affected with PMD were found to have a copy of PLP on the short arm of the X chromosome, in addition to a normal copy on Xq22. In the first family, the extra copy was first detected by the presence of heterozygosity of the AhaII dimorphism within the PLP gene. The results of FISH analysis showed an additional copy of PLP in Xp22.1, although no chromosomal rearrangements could be detected by standard karyotype analysis. Another three affected males from the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromosome. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reported, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identification of three separate families in which PLP is duplicated at a noncontiguous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.
Subject(s)
Gene Dosage , Gene Duplication , Mutagenesis, Insertional/genetics , Myelin Proteolipid Protein/genetics , Pelizaeus-Merzbacher Disease/genetics , X Chromosome/genetics , Child , Child, Preschool , Chromosome Inversion , Chromosomes, Artificial, Yeast/genetics , Cytogenetic Analysis , Exons/genetics , Female , Genes, Duplicate/genetics , Heterozygote , Humans , In Situ Hybridization, Fluorescence , Infant , Male , Pedigree , Polymorphism, Single-Stranded Conformational , Recombination, Genetic/geneticsABSTRACT
We report on two patients with rare 6q duplications. The karyotype of patient 1 is 46,XY,dup(6)(q21q23.3). The karyotype of patient 2 is 46,XX,dup(6)(q21.15q23.3). These two patients have some nonspecific physical findings in common including a depressed nasal bridge, epicanthal folds, mild heart defects, and developmental delay, but each had other congenital anomalies.
Subject(s)
Abnormalities, Multiple/genetics , Chromosome Aberrations , Chromosome Disorders , Chromosomes, Human, Pair 6 , Developmental Disabilities/genetics , Eyelids/abnormalities , Female , Heart Defects, Congenital/genetics , Humans , Infant , Infant, Newborn , Karyotyping , Nose/abnormalitiesSubject(s)
DNA, Mitochondrial/genetics , DNA/genetics , Muscular Dystrophies/genetics , Child , Chromosomes, Human, Pair 15 , DNA/analysis , DNA, Mitochondrial/analysis , Female , Humans , Indiana , MaleABSTRACT
We report a G-->A transition at nucleotide 431 of the proteolipid protein gene (PLP) results in a nonsense codon in a family with an unusual form of Pelizaeus-Merzbacher disease (PMD). The mutation, which creates a second AluI restriction site, results in a nonsense mutation in PLP. The clinical picture resembles somewhat that of X-linked spastic paraplegia (SPG). It differs from this and both the classical and connatal forms of PMD in that it is relatively mild in form, onset is delayed beyond age 2 years, nystagmus is absent, tremors are prominent, mental retardation is not severe, some patients show dementia or personality disorders, the disease is progressive rather than static in some, and several females show signs of disease. The nonsense mutation, which is in exon 3B, should block the synthesis of normal PLP but spare DM20, the isoform whose persistence has been associated with mild forms of PLP-associated disease in both humans and mice.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Exons/genetics , Myelin Proteolipid Protein/genetics , Point Mutation , Adolescent , Adult , DNA Primers , Female , Genetic Linkage , Humans , Male , Pedigree , Polymorphism, Genetic , Polymorphism, Single-Stranded Conformational , Sequence Analysis, DNAABSTRACT
A 23-year-old man with Pelizaeus-Merzbacher disease had a novel mutation, C344A (Thr115Lys), in exon 3 of the proteolipid protein gene (PLP) His mother, heterozygous for the mutation, developed progressive personality change and a gait disorder in her mid-20s. Her MRI at age 53 showed a diffuse severe leukodystrophy. This report extends the phenotypic range of disease due to PLP gene mutations to include adult-onset dementia in females.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Proteolipids/genetics , Adult , Age of Onset , Brain/pathology , Diffuse Cerebral Sclerosis of Schilder/pathology , Female , Humans , Male , Middle Aged , MutationABSTRACT
Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder of the central nervous system. Many cases of PMD can be attributed to defects in the proteolipid protein gene (PLP). To date, with one exception, each family has had either no or a unique mutation in one of the seven exons of PLP. We describe a new missense mutation in exon 2 of the PLP gene of an affected individual. This mutation codes for Ile instead of Thr at codon 42. The point mutation originated in the X chromosome of the maternal great-grandfather of the propositus. This was determined from the pattern of inheritance of the AhaII polymorphism and a series of microsatellite markers that are localized near PLP at Xq22.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Myelin Proteolipid Protein/genetics , Point Mutation , X Chromosome , Adult , Base Sequence , DNA Primers , Deoxyribonucleases, Type II Site-Specific , Exons , Family , Female , Genetic Markers , Humans , Infant, Newborn , Isoleucine , Male , Molecular Sequence Data , Polymorphism, Genetic , Polymorphism, Restriction Fragment Length , ThreonineSubject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Myelin Proteins/genetics , Point Mutation , Amino Acid Sequence , Asparagine , Base Sequence , Child, Preschool , DNA Primers , Exons , Female , Humans , Lysine , Male , Molecular Sequence Data , Myelin Proteolipid Protein , Polymerase Chain Reaction , Polymorphism, GeneticABSTRACT
Pelizaeus-Merzbacher disease has been known since 1885. It is characterized by severe dysmyelination of the central nervous system. We describe a new mutation in exon 6 of the proteolipid protein gene in a 9-year-old boy with severe connatal Pelizaeus-Merzbacher disease.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Exons/genetics , Myelin Proteins/genetics , Point Mutation , Base Sequence , Child , Electrophoresis, Polyacrylamide Gel , Genes , Humans , Male , Molecular Sequence Data , Myelin Proteolipid Protein , Polymerase Chain Reaction , Polymorphism, Single-Stranded Conformational , X ChromosomeABSTRACT
We studied a female infant with clinical signs of Pelizaeus-Merzbacher disease (PMD), who has a familial mutation (C41-->T) in exon 2 of the proteolipid protein gene (PLP), and selected relatives. While the carrier mother and grandmother of the proposita currently are neurologically normal and show normal T2 magnetic resonance imaging (MRI) of the brain, the infant has a neurological picture, MRIs, and brain auditory evoked response (BAER) consistent with that diagnosis. The data here presented show that PMD can occur in females carrying a mutation in the PLP gene. Our experience with the MRIs of this patient, her mother and grandmother, and those of a previously reported family [Pratt et al.: Am J Med Genet 38:136-139, 1991] show that molecular genetic analysis and not MRI is the appropriate means for carrier detection.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Myelin Proteins/genetics , Point Mutation , Brain/pathology , Child, Preschool , Diffuse Cerebral Sclerosis of Schilder/diagnosis , Diffuse Cerebral Sclerosis of Schilder/physiopathology , Evoked Potentials, Auditory, Brain Stem , Exons , Female , Genetic Carrier Screening , Genetic Linkage , Heterozygote , Humans , Magnetic Resonance Imaging , Male , Myelin Proteolipid Protein , Pedigree , Phenotype , Polymerase Chain Reaction , X ChromosomeABSTRACT
Single-strand conformational polymorphism analysis of an affected male with Pelizaeus-Merzbacher disease (PMD) showed a slight change in mobility of amplified exon 5 of the proteolipid protein (PLP) gene. The exon was sequenced and a G-->A transition at codon 216 was found. This mutation eliminates a BstNI restriction site and creates a MaeI restriction site. In 1989, Gencic et al. reported a mutation that destroyed the same BstNI site, but resulted in a substitution at codon 215 [Am J Hum Genet 45:435-442]. The mutation we report here is also present in the patient's mother and her male fetus as determined by polymerase chain reaction analysis of amniocytes.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Myelin Proteins/genetics , Point Mutation , Child, Preschool , Exons , Female , Genetic Linkage , Humans , Male , Myelin Proteolipid Protein , Pedigree , Pregnancy , X ChromosomeABSTRACT
We describe an in-frame deletion of parts of exons 3 and 4 of the proteolipid protein gene (PLP), with all of the intervening sequence, in a 3-generation family with Pelizaeus-Merzbacher disease. The mutation removes 49 amino acids of the PLP.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Myelin Proteins/genetics , Sequence Deletion , Amino Acid Sequence , Base Sequence , DNA/genetics , DNA Primers/genetics , Exons , Female , Humans , Infant, Newborn , Male , Molecular Sequence Data , Myelin Proteolipid Protein , PedigreeABSTRACT
The purpose of this study was to confirm linkage of the proteolipid protein gene (PLP) and Pelizaeus-Merzbacher disease (PMD). A T-->A transversion in nucleotide pair 35 of exon 4 of PLP was found in a large Finnish kindred with PMD. This mutation results in the substitution Val165-->Glu165. We used a combination of single-strand conformational polymorphism and PCR primer extension to determine the presence or absence of the point mutation in family members. A lod score of 2.6 (theta = 0) was found for linkage of the gene and the disease. We examined 101 unrelated X chromosomes and found none with the transversion. This is the second report of linkage of PMD to a missense mutation in PLP. These findings support the hypothesis that PMD in this family is a result of the missense mutation present in exon 4 of PLP.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Genetic Linkage , Myelin Proteins/genetics , Point Mutation , Base Sequence , DNA Mutational Analysis , DNA, Single-Stranded , Female , Finland , Humans , Male , Molecular Sequence Data , Myelin Proteolipid Protein , Pedigree , Polymorphism, Genetic , X ChromosomeABSTRACT
Pelizaeus-Merzbacher disease (PMD) has been recognized as a clinical entity for more than a century. It has gradually become apparent that the disorder is a dysmyelination, in distinction to demyelinating conditions such as adrenoleukodystrophy. The failure to deposit myelin is due to decreased production of its chief protein, proteolipid protein (PLP). In about 30% of patients with the diagnosis of PMD there is a mutation in the coding portion of the proteolipid protein gene, PLP. This gene is located at Xq22 so the disease in these families shows an X-linked pattern of inheritance. The expression of the mutant gene is generally recessive, but some mutations are expressed frequently in females. At least some patients with PMD that do not show mutations in the coding region of PLP demonstrate linkage between the disease and PLP. As additional mutations in PLP are discovered, it is becoming apparent that the nosology of PLP-associated disease is changing. PMD now comprises a spectrum of disorders with similar but not necessarily identical clinical pictures. Some of these disorders may be certain forms of X-linked paraplegia, SPG2. Finally, some diseases that look like PMD may not be X-linked.
Subject(s)
Diffuse Cerebral Sclerosis of Schilder/genetics , Amino Acid Sequence , Base Sequence , Humans , Molecular Sequence Data , Myelin Proteins/genetics , Myelin Proteolipid ProteinABSTRACT
A C--greater than G transversion has been found in exon 3 of the PLP gene of affected males and their mother in a single sibship with Pelizaeus-merzbacher disease (PMD). The transversion should not result in an amino acid change in the protein but it does result in the loss of a HaeIII restriction endonuclease cleavage site. It is concordant with the disease in this family. One-hundred-ten unrelated X chromosomes are negative for this mutation. No other sequence defect was found in the PLP exons of the affected males. The cause of disease in this family remains unknown, but the association between this rare mutation and PMD is intriguing. The mutation can serve as a marker for following segregation of the PLP gene.