Lysosomal Storage Disorder Screening Implementation: Findings from the First Six Months of Full Population Pilot Testing in Missouri

Precision newborn screening for lysosomal disorders

“…recapitulated the charges actually billed to health insurance plans on behalf of patients with whom she personally interacted while working in a state offering newborn screening for lysosomal disorders. 12 This review showed that just the initial encounter to work up an abnormal referral could cost an average of $6,823 per case (range $4,242-13,438, N = 10) for the combined expenses of office visits, counseling, procedures, laboratory tests, and comprehensive molecular genetic testing. A linear extrapolation of these charges to a hypothetical nationwide implementation (~4.2 million births) when the false-positive rate is not better than a 0.1-0.5% range may translate into $28-143 million of unnecessary expenses per year.…”

“…10 Other lysosomal disorders, particularly galactocerebrosidase (GALC) deficiency (Krabbe disease), 11 have been turned down by the committee because they lacked evidence of net benefits. However, advocacy efforts and legislative mandates have propelled six states to begin screening for Krabbe disease and other lysosomal disorders, [12][13][14] but reports of outcomes and performance have not been encouraging. [15][16][17] In 2015, the legislature of the Commonwealth of Kentucky passed bill KRS 214.155, mandating screening for Krabbe disease.…”

“…18 This request was not fulfilled because conventional interpretation methods of a single marker (cutoff, percent of daily mean) are not suited to differentiation of affected patients from individuals who are either heterozygous or carry pseudo-deficiency alleles. [12][13][14][15] The laboratory made a counter-proposal to perform a profile of six lysosomal enzyme activities using commercially available substrates, inclusive of the primary markers of Pompe disease and MPS I, integrated with additional analytes and second-tier tests as needed. This new plan, characterized by the expanded scope of testing and reporting of three conditions, was agreeable to both Kentucky and Mayo Clinic.…”

Newborn screening for Krabbe disease in New York State: the first eight years’ experience

“…21,25,26 Although the Secretary's Advisory a Variants are classified as into five categories using ACMG guidelines 41 : P/LP = pathogenic/likely pathogenic mutations (including "PVS1 null variants" such as large deletions, frameshift mutations, mutations at canonical splice sites, the extension mutation, and small in-frame deletion); p.T96A; p.Y303C; "Other" (all other rare variants (some of which have been reported in KD patients) and variants of unknown significance, primarily missense variants, but also rare synonymous mutations near exon/intron boundaries and rare 5′/3′UTR variants); or "−" (wild-type or polymorphisms including p.D94= and p.V320M). b Genotype phase estimated from parental data, where available.…”

“…25 Missouri has recently begun screening, 26 and several other states have pending mandates to screen KD and/or other LSDs. 16 Here, we describe our two-tiered enzyme and molecular screening assay and provide results from the first 1.9 million infants screened over the course of 8 years.…”