Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
2000-01-26
2003-05-20
Jones, W. Gary (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S023100, C536S024300, C536S024330
Reexamination Certificate
active
06566061
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to genetic polymorphisms that are associated with neuropsychiatric disorders and associated conditions including hypothyroidism.
BACKGROUND OF THE INVENTION
Over 2000 human pathological syndromes are known to result from DNA polymorphisms including insertions, deletions, multiplications and nucleotide substitutions. Finding genetic polymorphisms in individuals and following these variations in families provides a means to confirm clinical diagnoses and to diagnose both predispositions and disease states in carriers, preclinical and subclinical affected individuals. Counseling based upon accurate diagnoses allows patients to make informed decisions about potential parenting, ongoing pregnancy, and early intervention in affected individuals.
Polymorphisms associated with pathological syndromes are highly variable and, consequently, can be difficult to identify. Further, normal polymorphic nucleotide changes can complicate detection of abnormal alleles with changes at different nucleotides. Because multiple alleles within genes are common, one must distinguish disease syndrome-related alleles from neutral (non-disease-related) polymorphisms. Most alleles result from neutral polymorphisms that produce indistinguishable, normally active gene products or express normally variable characteristics like eye color. In contrast, some polymorphic alleles are associated with clinical diseases such as sickle cell anemia. Moreover, the structure of disease-related polymorphisms are highly variable and may result from a single point mutation such as occurs in sickle cell anemia, or from the expansion of nucleotide repeats as occurs in fragile X syndrome and Huntington's chorea.
Once a polymorphism or region of interest is identified, a wide variety of technologies exist which may be employed in the diagnosis of heritable syndromes. Traditionally, the diagnosis of such syndromes relied upon enzyme activity testing, statistical analysis, or invasive diagnostic procedures. Recent advances in DNA and related technologies including restriction fragment length polymorphism (RFLP) analysis, the polymerase chain reaction (PCR) and monoclonal or polyclonal antibody based assays provide additional rapid and highly accurate methods to screen for the presence of polymorphisms associated with heritable pathologies.
Among the different polymorphisms, the presence of unstable DNA sequences, such as the expansion of simple nucleotide sequence repeats in genomic DNA, has recently been implicated as a mechanism leading to a number of genetic disorders including pathologies associated with neuropsychiatric disorders such as mental retardation. Mental retardation (MR), which can be generally defined as a slowness or developmental impairment associated with adaptive behavior, is a prominent feature of many neurodevelopmental syndromes. MR is a lifelong disability that can place extreme demands on the families and on the health care system in general. Information obtained from the Incidence and Prevalence Database estimates that there are 6 million persons in the U.S. (3% of the population) with mental retardation. MR can be categorized as mild mental retardation (MMR, IQ 50-70) or as severe mental retardation (SMR, IQ less than 50). It is noted that SMR can be further subcategorized. An average SMR prevalence rate per 1000 people is thought to be as follows: ages 0-4, 1.7; ages 5-9, 2.8; ages 10-14, 3.6; ages 15-19, 4.0; ages 20-29, 3.8; ages 30-39, 3.3; 40-49, 2; ages 50-59, 1.2; ages over 60, 1.0. In 1977, nearly 150,000 adults with mental retardation were institutional residents; by 1992 their numbers had declined by 48% to just under 78,000.
The diagnosis of SMR does not usually occur in the first few years of life, rather it is usually identified later, typically at the school age years. The explanation why there is decreasing prevalence rates in the older age has been attributed to a higher than average mortality among the severely mentally retarded and possibly due to errors in the method used in gathering the data. Approximately one-half of the MR studies have shown rates of MR to be gender-specific. For SMR, the male-to-female ratio, there has been observed a 20% excess of males, which is thought to be due to sex-linked genetic factors.
Due to the prevalence of mental retardation (MR) and its pattern of heritability, the identification of chromosomal regions that are associated with MR pathologies has been the focus of significant research. Mental retardation affects approximately 1% of the U.S. population with mutations in the X-chromosome estimated to cause between 30-50% of these cases (Glass, I. A., (1991) X linked mental retardation. J Med Genet 28:361-371). The genetic mechanisms involved in a number of these X-linked syndromes have been identified and include repetitive DNA expansion in Fragile X (Verkerk, et al., “Identification of a gene (FMR-1) containing a CGG repeat coincident with a fragile X breakpoint cluster region exhibiting length variation in fragile X syndrome”, Cell 65:905 (1991)) and FRAXE (Gecz, et al., “Identification of the gene FMR2, associated with FRAXE mental retardation”, Nat Genet 13:105-108 (1996)), microdeletions (Billuart, et al., “Identification by STS PCR screening of a microdeletion in Xp21.3-22.1 associated with non-specific mental retardation”, Hum Mol Genet 5:977-979 (1996)), and point mutations in the Mental retardation, Aphasia, Shuffling gait, and Adducted thumbs (MASA) syndrome (Schrander-Stumpel, et al., “Spectrum of X-linked hydrocephalus (HSAS), MASA syndrome, and complicated spastic paraplegia (SPG1): clinical review with six additional families”, Am J Med Genet 57:107-116 (1995)) and Corpus callosum hypoplasia, Retardation, Adducted thumbs, Spastic paraplegia and Hydrocephalus syndrome (CRASH) (Fransen, et al., “CRASH syndrome: clinical spectrum of corpus callosum hypoplasia, retardation, adducted thumbs, spastic paraparesis and hydrocephalus due to mutations in one single gene”, Eur J Hum Genet 3:273-284 (1995)). While this research has provided significant insight into these X-linked syndromes, the causes of the majority of MR remain idiopathic at the current time.
The identification and characterization of specific polymorphisms associated with heritable syndromes such as MR are crucial components in the design of informative diagnostic assays. By identifying specific regions in the human genome which contain disease related polymorphisms, statistical analysis of the prevalence and penetrance of the syndrome is possible. Further, as different formulas are utilized for the assessment of autosomal recessive, autosomal dominant, and X-linked genetic diseases, the identification of the chromosomal location of the polymorphism is a crucial factor in the assessment of pedigree related risk analysis. Such information allows accurate risk assessments to take into account 1) the number of different alleles at each gene locus, 2) the relative frequency of each allele in the population (the most informative have more than one common allele), and 3) whether alleles are distributed randomly throughout the population. As technologies for assessing the presence or absence of a specific polymorphism or polymorphic region are well developed, the primary limitation on diagnostic assays is the lack of information on polymorphisms associated with different pathologies.
What is needed in the art is the identification of novel regions in the human genome which contain polymorphisms that are associated with heritable syndromes. The identification of such regions is particularly useful in that it allows for the design of informative assays and diagnostic tests for susceptibility factors associated with the occurrence of such syndromes. The existence of informative assays which test for the presence of such heritable factors allows the accurate diagnosis of affected individuals and provides these individuals and health care professionals with the knowledge necessary to make informed decisions based on the pres
Delisi Lynn
Ginns Edward I.
Philibert Robert A.
Goldberg Jeanine
Jones W. Gary
Merchant & Gould P.C.
The University of Iowa, as represented by the University of Iowa
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