The National Institutes of Health and the Office of Rare Diseases plan to procure on a sole source basis with the University of Chicago Genetics Genetic Services Laboratory, to develop new genetic tests under the Office of Rare Diseases (ORD) Collaboration, Education, and Test Translation Program for Rare Genetic Diseases. The program that promotes new genetic test development and access to clinical laboratories for the public. This program accelerates the translation of genetic tests from research laboratory to Clinical Laboratory Improvement Amendments (CLIA)-certified clinical laboratories. The University of Chicago Genetics Genetic Services Laboratory will establish the first available molecular genetic testing in a CLIA approved clinical laboratory for the rare diseases described below and/or alternative rare diseases for test translation within the budget outlined.Description of Genetic Disorders and Genes for Test Translation: Genetic Disorder: Autosomal Recessive Polymicrogyria Gene: GPR56 Polymicrogyria is a disorder of cortical brain development that can result in a spectrum of developmental problems from birth ranging from mild cognitive, learning problems to severe mental retardation, cerebral palsy and seizure disorders. Polymicrogyria, due to a mutation of the GPR56 gene is a rare autosomal recessive genetic disorder. GPR56, a family B G protein-coupled receptor, is widely expressed throughout the body and appears to be essential during human cerebral cortical development and patterning. Current testing is only available in Germany. Testing is not available in a CLIA-approved laboratory in the United States. Thus, affected individuals or at-risk family members do not have access to genetic testing except on a research basis, which means that testing results cannot be reported back to the individual. The establishment of testing in a clinical laboratory would allow for presymptomatic, prenatal, and/or carrier testing. Genetic Disorder: Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (CHILD) syndrome Gene: NSDHL CHILD (congenital hemidysplasia with ichthyosiform erythroderma and limb defects) syndrome is a rare X-linked dominant inherited disorder characterized by birth defects of several organ systems, including the skin, the viscera, and the musculoskeletal and central nervous systems. Patients with CHILD syndrome have been found to have a mutation in the NSDHL gene encoding for an enzyme in the cholesterol biosynthetic pathway. Greater than two thirds of cases reported occur in females. The gene has been localized to Xq28 and encodes for 3beta-hydroxy sterol dehydrogenase involved in the oxidative decarboxylation of sterol C-4 methyl groups. Both heterozygous nonsense and heterozygous missense mutations have been identified. Currently only analyte measurement (biochemical testing) is available. Molecular Testing is not available in a CLIA-approved laboratory in the United States. Thus, affected individuals or at-risk family members do not have access to genetic testing except on a research basis, which means that testing results cannot be reported back to the individual. The establishment of testing in a clinical laboratory would allow for presymptomatic, prenatal, and/or carrier testing. Genetic Disorder: X-Linked Alport Syndrome (XLAS) Gene: COL4A5 Alport syndrome is characterized by renal, cochlear, and ocular involvement. About 80% of Alport syndrome is caused by mutations in COL4A5 and is inherited in an X-linked manner. The hallmark of Alport syndrome is microscopic hematuria (microhematuria). Males with X-linked Alport syndrome (XLAS) have persistent microhematuria from early in life. Over 90% of females with XLAS have microscopic hematuria. All males with XLAS develop proteinuria and eventually progressive renal insufficiency, which leads to end-stage renal disease (ESRD). Overall, about 60% reach ESRD by age 30 years, and 90% by age 40 years. About 10% of females with XLAS develop ESRD by age 40, and about 30% by age 60. Diminished hearing is usually detectable by late childhood or early adolescence in boys with XLAS; the hearing loss is progressive and about 80%-90% of these males have sensorineural deafness by age 40 years. In females with XLAS, hearing loss is less frequent and tends to occur later in life. The spectrum of ocular lesions include anterior lenticonus which is virtually pathognomonic of Alport syndrome; other ocular findings include a maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region, corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. Currently, the only available genetic testing is through laboratories in Germany and Belgium. Molecular Testing is not available in a CLIA-approved laboratory in the United States. The establishment of testing in a clinical laboratory would allow for presymptomatic, prenatal, and/or carrier testing. 1) Develop the Collaborative Team for genetic test translation: The University of Chicago will develop collaborations with appropriate researchers, clinicians and advocacy appropriate for the rare disease identified for translation 2) Develop the Molecular Testing Platform: The University of Chicago Genetics Diagnostic Laboratory will establish and make available molecular testing for the rare diseases identified for genetic test translation. In addition, the University of Chicago will assure: - Validation of Test Results: Sequence based assays are largely considered self validating. The laboratory will obtain samples with known mutations to test in a blinded fashion for formal test validation purposes prior to their implementation. This laboratory is experienced in offering full sequencing as a diagnostic test. - Plans to Analyze Variants of Unknown Significance (VOUS): The University of Chicago will follow appropriate guidelines of the CETT Program for addressing VOUS 3) Develop Educational Materials for Clinicians, patients and Geneticists regarding use of genetic testing in the diagnosis of the rare diseases under genetic test translation 4) Create/expand a Gene Review document within 1 year of establishing genetic testing for the rare diseases identified for genetic test translation 4) Collect and store de-identifiable clinical description and genetic mutation information obtained at the time of genetic testing. Deliverables ? CLIA-certified molecular diagnostic testing for the three rare diseases described above or alternative rare diseases defined through the period of performance will be made available, as evidenced by a public advertisement or website announcement to that effect. We expect that this will occur within 12 months of the receipt of payment for this service. ? Development of Educational Materials for clinicians and individuals and families with the rare diseases translated to clinical tests to accompany the establishment of clinical genetic testing for these rare diseases. ? Plan for collecting and storing non-identifiable genetic information regarding the clinical genetic testing over time. The NCBI, NLM is committed to working with each rare genetic testing collaborating team through the CETT Program in developing the collection and storage plan. ? Commitment to develop Gene Review within 1 year of funding for rare disease genetic test development ? Commitment to 5 year reporting of genetic test usage, to include: o Number of molecular tests ordered and which genes were identified with the molecular mutation o Number of samples with VOUS for which research groups are contacted for help with interpretation and/or follow-up parental samples are obtained to help with interpretation o Information on the use and value of the educational materials to help clinicians and families to understand the genetic test However, if any other interested party believes that they can meet the requirements they may submit a statement of capabilities. The capability statement and any other information furnished must be in writing, and must contain detailed documentation to allow the government to perform a proper evaluation. Respondents will not be notified of evaluation results. The closing date will be 10 calendar days after publication. All vendors/prospective contractors must be registered with the Central Contractor?s Registration (www.ccr.gov) prior to award date. If not registered or active by that date, vendor proposals will be considered non responsive.
