Mendelian diseases collectively affect 13 million people in the US, accounting for ~20% of infant mortality and ~18% of pediatric hospitalizations36,37,38,39,40
Diagnostic testing in potentially affected children
Simultaneous diagnostic testing for 595 recessive childhood diseases is anticipated to have several public health impacts: 1). Extension of the prevention, diagnosis, and treatment benefits demonstrated for conventional genetic testing to hundreds of recessive diseases for which testing is not available today; 2). Reduction in time-to-diagnosis, particularly in illnesses where the differential diagnosis is broad and the conventional approach is serial univariate testing. Serial univariate testing can take over a year, delaying timely intervention or counseling. The initial turnaround time of the test will be 4 weeks. 3). Reduction in cost of diagnosis. The average cost per patient of serial univariate molecular diagnostic testing is ~$10,000 at our institution. The test is anticipated to cost ~$600. 4). Increased rate of definitive molecular diagnosis. Less than 50% of patients undergoing serial univariate molecular diagnostic testing receive a molecular diagnosis. This is anticipated to increase with test use, particularly in illnesses where the differential diagnosis is broad, such as mitochondrial myopathies or intellectual disability. Timely diagnosis of affected individuals has several potential benefits:
1. Prevention of death or markedly diminished disease severity where curative treatments are available. Quite a large number of recessive diseases have specific therapies. Neonatal diagnosis and treatment of phenylketonuria (PKU) and congenital hypothyroidism prevent severe intellectual disability. Likewise, death is prevented in certain forms of congenital adrenal hyperplasia (CAH), medium chain acyl-coA dehydrogenase deficiency (MCAD), and galactosemia (OMIM #230400).
2. Genetic counseling of patients and families about risks for relatives and in additional offspring.
3. Improvement in quality of life in disorders where treatments are ameliorative. While many recessive diseases lack curative treatments, timely diagnosis nevertheless allows specific interventions that can substantially improve quality of life. Such interventions may slow disease progression, lessen symptoms, prevent complications or improve function in affected organ systems.
4. Substantial psychosocial benefits with respect to anxiety, self-image, uncertainty and lifestyle decisions.
5. Multiplexed testing allows rule-out of differential diagnoses, decreasing unnecessary treatments.
Use of the research version of the test revealed that 27% of literature mutations are common polymorphisms or misannotated1. Thus, it is critical to establish a clinical grade mutation database for recessive illnesses. Implementation of the test for diagnosis in affected children will, with time, improve the quality and quantity of annotated mutations, particularly for diseases that for which no molecular test is available currently.
In addition, test results have a cumulative potential to inform an understanding of disease mechanisms. In each individual with a Mendelian disorder, the specific mutations impact the age of onset, disease severity, rates of progression, distribution of affected organs, complications, pleiotropy and outcomes. Only in diseases for which molecular diagnosis is undertaken can such knowledge be accumulated. A broad understanding of genotype-phenotype relationships can enable individualized care of patients with recessive diseases. This can potentially include individualized treatment intensity and prediction of disease progression, severity and likely complications. Thus, in the long term, the test, when performed in a research setting, can allow identification of genotype-phenotype relationships that allow conveyance of individualized diagnostic information.
Initial experience with the test has revealed the existence of novel modifier mutations and pleiotropy in patients with recessive illnesses (Kingsmore et al., submitted). Only through multiplexed molecular testing can such knowledge be accumulated. A broad understanding of modifier genes can further enable individualized care of patients with recessive diseases. Thus, in the long term, the test, when performed in a research setting, can allow identification of modifier genes that allow conveyance of individualized diagnostic information.
Finally, timely molecular diagnosis can allow intervention before organ decompensation, when treatment is likely to alter outcomes. Currently, study of new therapies for rare disorders are hampered by diagnosis after organ damage and low rates of ascertainment. Timely diagnosis can permit regional referral of affected individuals for specialized treatment.
It should be noted that substantiation of the potential public health impacts in prevention, diagnosis, or treatment of recessive childhood illnesses is needed. Such assessments should include measurement of cost effectiveness including costs of follow up of ambiguous test results and counseling.