Mortality in a neonate with molybdenum cofactor deficiency illustrates the need for a comprehensive rapid precision medicine system

Stephen F Kingsmore, Nanda Ramchandar, Kiely James, Anna-Kaisa Niemi, Annette Feigenbaum, Yan Ding, Wendy Benson, Charlotte Hobbs, Shareef Nahas, Shimul Chowdhury, David Dimmock, Stephen F Kingsmore, Nanda Ramchandar, Kiely James, Anna-Kaisa Niemi, Annette Feigenbaum, Yan Ding, Wendy Benson, Charlotte Hobbs, Shareef Nahas, Shimul Chowdhury, David Dimmock

Abstract

Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.

Keywords: congenital horizontal nystagmus; diffuse swelling of cerebral white matter; generalized tonic seizures; hypouricemia; infantile encephalopathy; poor suck; upper limb spasticity.

© 2020 Kingsmore et al.; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.
Figure 1.
Components of the proposed comprehensive system for delivery of newborn precision medicine.

References

    1. Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A. 2019. GeneReviews®. University of Washington, Seattle.
    1. American College of Medical Genetics ACT Sheets and Confirmatory Algorithms. 2019.
    1. Arenas M, Fairbanks LD, Vijayakumar K, Carr L, Escuredo E, Marinaki AM. 2009. An unusual genetic variant in the MOCS1 gene leads to complete missplicing of an alternatively spliced exon in a patient with molybdenum cofactor deficiency. J Inherit Metab Dis 32: 560–569. 10.1007/s10545-009-1151-7
    1. Aziz N, Zhao Q, Bry L, Driscoll DK, Funke B, Gibson JS, Grody WW, Hegde MR, Hoeltge GA, Leonard DG, et al. 2015. College of American Pathologists’ laboratory standards for next-generation sequencing clinical tests. Arch Pathol Lab Med 139: 481–493. 10.5858/arpa.2014-0250-CP
    1. Berry MA, Shah PS, Brouillette RT, Hellmann J. 2008. Predictors of mortality and length of stay for neonates admitted to children's hospital neonatal intensive care units. J Perinatol 28: 297–302. 10.1038/sj.jp.7211904
    1. Berry SA. 2015. Newborn screening. Clin Perinatol 42: 441–453. 10.1016/j.clp.2015.03.002
    1. Chambers DA, Feero WG, Khoury MJ. 2016. Convergence of implementation science, precision medicine, and the learning health care system: a new model for biomedical research. J Am Med Assoc 315: 1941–1942. 10.1001/jama.2016.3867
    1. Clark MM, Hildreth A, Batalov S, Ding Y, Chowdhury S, Watkins K, Ellsworth K, Camp B, Kint CI, Yacoubian C, et al. 2019. Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation. Sci Transl Med 11: eaat6177 10.1126/scitranslmed.aat6177
    1. Database of Human Structural Variants dbVar. 2019.
    1. Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, Cakici JA, Benson W, Kaplan RH, Kronick R, et al. 2018. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med 3: 10 10.1038/s41525-018-0049-4
    1. French CE, Delon I, Dolling H, Sanchis-Juan A, Shamardina O, Mégy K, Abbs S, Austin T, Bowdin S, Branco RG, et al. 2019. Whole genome sequencing reveals that genetic conditions are frequent in intensively ill children. Intensive Care Med 45: 627–636. 10.1007/s00134-019-05552-x
    1. Hinderhofer K, Mechler K, Hoffmann GF, Lampert A, Mountford WK, Ries M. 2017. Critical appraisal of genotype assessment in molybdenum cofactor deficiency. Inherit Metab Dis 40: 801–811. 10.1007/s10545-017-0077-8
    1. Kikuchi K, Hamano S, Mochizuki H, Ichida K, Ida H. 2012. Molybdenum cofactor deficiency mimics cerebral palsy: differentiating factors for diagnosis. Pediatr Neurol 47: 147–149. 10.1016/j.pediatrneurol.2012.04.013
    1. Kingsmore SF, Cakici JA, Clark MM, Gaughran M, Feddock M, Batalov S, Bainbridge MN, Carroll J, Caylor SA, Clarke C, et al. 2019. NSIGHT2: a randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in seriously ill infants. AJHG 105: 719–733. 10.1016/j.ajhg.2019.08.009
    1. March of Dimes. 2016. The March of Dimes data book for policy makers: maternal, infant and child health in the United States 2016.
    1. Matthijs G, Souche E, Alders M, Corveleyn A, Eck S, Feenstra I, Race V, Sistermans E, Sturm M, Weiss M, et al. 2016. Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet 24: 2–5. 10.1038/ejhg.2016.63
    1. Mechler K, Mountford WK, Hoffmann GF, Ries M. 2015. Ultra-orphan diseases: a quantitative analysis of the natural history of molybdenum cofactor deficiency. Genet Med 17: 965–970. 10.1038/gim.2015.12
    1. Mestek-Boukhibar L, Clement E, Jones WD, Drury S, Ocaka L, Gagunashvili A, Le Quesne Stabej P, Bacchelli C, Jani N, Rahman S, et al. 2018. Rapid paediatric sequencing RaPS: comprehensive real-life workflow for rapid diagnosis of critically ill children. J Med Genet 55: 721–728. 10.1136/jmedgenet-2018-105396
    1. Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, Marrs T, Corder S, Krivohlavek L, Walter A, et al. 2015. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med 7: 100 10.1186/s13073-015-0221-8
    1. Murphy SL, Xu J, Kochanek KD, Arias E. 2018. Mortality in the United States, 2017. NCHS Data Brief.
    1. Online Mendelian Inheritance in Man. 2019.
    1. Pearce C, Goettke E, Hallowell N, McCormack P, Flinter F, McKevitt C. 2019. Delivering genomic medicine in the United Kingdom National Health Service: a systematic review and narrative synthesis. Genet Med 10.1038/s41436-019-0579-x
    1. Pertea M, Lin X, Salzberg SL. 2001. GeneSplicer: a new computational method for splice site prediction. Nucleic Acids Res 29: 1185–1190. 10.1093/nar/29.5.1185
    1. Petrikin JE, Willig LK, Smith LD, Kingsmore SF. 2015. Rapid whole genome sequencing and precision neonatology. Semin Perinatol 39: 623–631. 10.1053/j.semperi.2015.09.009
    1. Petrikin JE, Cakici JA, Clark MM, Willig LK, Sweeney NM, Farrow EG, Saunders CJ, Thiffault I, Miller NA, Zellmer L, et al. 2018. The NSIGHT1-randomized controlled trial: rapid whole-genome sequencing for accelerated etiologic diagnosis in critically ill infants. NPJ Genom Med 3: 6 10.1038/s41525-018-0045-8
    1. Reese MG, Eeckman FH, Kulp D, Haussler D. 1997. Improved splice site detection in genie. J Comp Biol 4: 311–323. 10.1089/cmb.1997.4.311
    1. Rehm HL, Bale SJ, Bayrak-Toydemir P, Berg JS, Brown KK, Deignan JL, Friez MJ, Funke BH, Hegde MR, Lyon E. 2013. American College of Medical Genetics and Genomics clinical laboratory standards for next-generation sequencing. Genet Med 15: 733–747. 10.1038/gim.2013.92
    1. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, et al. 2015. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17: 405–424. 10.1038/gim.2015.30
    1. Roy S, Coldren C, Karunamurthy A, Kip NS, Klee EW, Lincoln SE, Leon A, Pullambhatla M, Temple-Smolkin RL, Voelkerding KV, et al. 2018. Standards and guidelines for validating next-generation sequencing bioinformatics pipelines: a joint recommendation of the Association for Molecular Pathology and the College of American Pathologists. J Mol Diagn 20: 4–27. 10.1016/j.jmoldx.2017.11.003
    1. Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Andraws N, Patterson ML, Krivohlavek LA, Fellis J, et al. 2012. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 4: 154ra135 10.1126/scitranslmed.3004041
    1. Schwahn BC, Van Spronsen FJ, Belaidi AA, Bowhay S, Christodoulou J, Derks TG, Hennermann JB, Jameson E, König K, McGregor TL, et al. 2015. Efficacy and safety of cyclic pyranopterin monophosphate substitution in severe molybdenum cofactor deficiency type A: a prospective cohort study. Lancet 386: 1955–1963. 10.1016/S0140-6736(15)00124-5
    1. Schwarz G, Santamaria-Araujo JA, Wolf S, Lee HJ, Adham IM, Gröne HJ, Schwegler H, Sass JO, Otte T, Hänzelmann P, et al. 2004. Rescue of lethal molybdenum cofactor deficiency by a biosynthetic precursor from Escherichia coli. Hum Mol Genet 13: 1249–1255. 10.1093/hmg/ddh136
    1. Smith LD, Willig LK, Kingsmore SF. 2015. Whole-exome sequencing and whole-genome sequencing in critically ill neonates suspected to have single-gene disorders. Cold Spring Harb Perspect Med 6: a023168 10.1101/cshperspect.a023168
    1. Stark Z, Lunke S, Brett GR, Tan NB, Stapleton R, Kumble S, Yeung A, Phelan DG, Chong B, Fanjul-Fernandez M, et al. 2018. Meeting the challenges of implementing rapid genomic testing in acute pediatric care. Genet Med 20: 1554–1563. 10.1038/gim.2018.37
    1. Therrell BL Jr, Schwartz M, Southard C, Williams D, Hannon WH, Mann MY, PEAS Organizing and Working Groups. 2010. Newborn screening system performance evaluation assessment scheme PEAS. Semin Perinatol 34: 105–120. 10.1053/j.semperi.2009.12.002
    1. Therrell BL, Padilla CD, Loeber JG, Kneisser I, Saadallah A, Borrajo GJ, Adams J. 2015. Current status of newborn screening worldwide: 2015. Semin Perinatol 39: 171–187. 10.1053/j.semperi.2015.03.002
    1. Topcu M, Coskun T, Haliloglu G, Saatci I. 2001. Molybdenum cofactor deficiency: report of three cases presenting as hypoxic-ischemic encephalopathy. J Child Neurol 16: 264–270. 10.1177/088307380101600406
    1. Weiner J, Sharma J, Lantos J, Kilbride H. 2011. How infants die in the neonatal intensive care unit: trends from 1999 through 2008. 2011. Arch Pediatr Adolesc Med 165: 630–634. 10.1001/archpediatrics.2011.102
    1. Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, Soden SE, Cakici JA, Herd SM, Twist G, et al. 2015. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med 3: 377–387. 10.1016/S2213-2600(15)00139-3
    1. Yeo G, Burge CB. 2004. Maximum entropy modeling of short sequence motifs with applications to RNA splicing signals. J Comput Biol 11: 377–394. 10.1089/1066527041410418
    1. Zahid M, Khan AH, Yunus ZM, Chen BC, Steinmann B, Johannes H, Afroze B. 2019. Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: a case series of patients presenting at a tertiary care hospital in Pakistan. J Pak Med Assoc 69: 432–436.

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