First Three Years' Experience of Mucopolysaccharidosis Type-I Newborn Screening in California.

OBJECTIVE: To report on the first 3 years of mucopolysaccharidosis type I (MPS I) newborn screening (NBS) in the large and diverse state of California. STUDY DESIGN: The California Genetic Disease Screening Program began universal NBS for MPS I on August 29, 2018. The screening uses a 2-tiered approach: an α-L-iduronidase (IDUA) enzyme activity assay followed by DNA sequencing for variants in the IDUA gene. RESULTS: As of August 29, 2021, 1 295 515 California newborns were screened for MPS I. In tier 1 of screening, 329 (0.025%) had an IDUA enzyme measurement below the cutoff and underwent tier-2 IDUA DNA sequencing. After tier 2, 146 (0.011%) newborns were screen positive, all of whom were referred to a metabolic Special Care Center for follow-up. After long-term follow-up, 7 cases were resolved as severe MPS I (Hurler syndrome) and 2 cases as attenuated MPS I for an MPS I birth prevalence of 1/143 946. DNA sequencing identified 107 unique IDUA variants among a total of 524 variants; 65% were known pseudodeficiency alleles, 25% were variants of uncertain significance, and 10% were pathogenic variants. CONCLUSIONS: As a result of a 2-tiered NBS approach, 7 newborns diagnosed with Hurler syndrome had received early treatment for MPS I. Continuation of California's long-term follow-up program will be crucial for further understanding the complex genotype-phenotype relationships of MPS I.

California's experience with SMA newborn screening: A successful path to early intervention.

BACKGROUND: Universal spinal muscular atrophy (SMA) newborn screening was implemented in California on June 24, 2020. OBJECTIVE: We describe California's experience with the first 18 months of SMA newborn screening, including our assay methodology, timeliness of screening and follow-up milestones, and clinical and epidemiological outcomes observed. METHODS: Dried blood spots are screened for SMA using multiplex real time polymerase chain reaction (RT-PCR) to detect deletions of exon 7 in the survival of motor neuron 1 (SMN1) gene. Short-term follow-up data is collected from clinical staff via an online data collection tool. RESULTS: In the first 18 months, 628,791 newborns from California's diverse population were tested for SMA. Thirty-four screened positive and were confirmed to have the disorder. Infants were referred, diagnosed, and treated at a median of 8, 12, and 33 days of life, respectively. Nearly all infants received the desired treatment modality, and 62% received treatment while still asymptomatic. CONCLUSIONS: SMA newborn screening is a highly sensitive and specific test which identifies infants with SMA early when treatment is most effective. Even with newborn screening's success in facilitating early intervention, there is still work to be done to expedite treatment, especially for infants with the most severe form of the disease.

Adrenoleukodystrophy Newborn Screening in California Since 2016: Programmatic Outcomes and Follow-Up.

X-linked adrenoleukodystrophy (ALD) is a recent addition to the Recommended Uniform Screening Panel, prompting many states to begin screening newborns for the disorder. We provide California's experience with ALD newborn screening, highlighting the clinical and epidemiological outcomes observed as well as program implementation challenges. In this retrospective cohort study, we examine ALD newborn screening results and clinical outcomes for 1,854,631 newborns whose specimens were received by the California Genetic Disease Screening Program from 16 February 2016 through 15 February 2020. In the first four years of ALD newborn screening in California, 355 newborns screened positive for ALD, including 147 (41%) with an ABCD1 variant of uncertain significance (VUS) and 95 males diagnosed with ALD. After modifying cutoffs, we observed an ALD birth prevalence of 1 in 14,397 males. Long-term follow-up identified 14 males with signs of adrenal involvement. This study adds to a growing body of literature reporting on outcomes of newborn screening for ALD and offering a glimpse of what other large newborn screening programs can expect when adding ALD to their screening panel.

Fred Lorey Passed Away.

To tackle the ever-increasing ambitions of the International Journal of Neonatal Screening (IJNS), in November 2019, we were looking for an Associate Editor to strengthen the Editorial board of IJNS [...].

The First Year Experience of Newborn Screening for Pompe Disease in California.

The California Department of Public Health started universal newborn screening for Pompe disease in August 2018 with a two-tier process including: (1) acid alpha-glucosidase (GAA) enzyme activity assay followed by, (2) GAA gene sequencing analysis. This study examines results from the first year of screening in a large and diverse screening population. With 453,152 screened newborns, the birth prevalence and GAA enzyme activity associated with various types of Pompe disease classifications are described. The frequency of GAA gene mutations and allele variants are reported. Of 88 screen positives, 18 newborns were resolved as Pompe disease, including 2 classic infantile-onset and 16 suspected late-onset form. The c.-32-13T>G variant was the most common pathogenic mutation reported. African American and Asian/Pacific Islander newborns had higher allele frequencies for both pathogenic and pseudodeficiency variants. After the first year of Pompe disease screening in California, the disease distribution in the population is now better understood. With the ongoing long-term follow-up system currently in place, our understanding of the complex genotype-phenotype relationships will become more evident in the future, and this should help us better understand the clinical significance of identified cases.

Providers' Perspectives on Treating Patients With Thalassemia.

In recent years, California has experienced a steady rise in Asian immigration which has led to a corresponding increased prevalence of clinically significant thalassemia in this state. As part of the Public Health Research, Education and Surveillance for Hemoglobinopathies emoglobinopathies project, a survey was developed to collect information from California providers who care for thalassemia patients in an effort to better understand their practice patterns, barriers to providing care, and educational needs. When asked about educational needs, providers most frequently expressed a desire for care and management guidelines (65.3%), health educational materials for patients (47.2%), and information on complications and clinical outcomes (32.1%). Only one quarter of providers (24.0%) reported that all of their thalassemia patients have a coordinated care plan. The increase in California thalassemia cases highlights the importance of provider knowledge to effectively serve the patients in their communities. Provider education and dissemination of treatment standards can not only improve knowledge about the disease but also increase awareness about the importance of coordinating care among a multidisciplinary team of specialists. Improvement in these areas will help achieve the overarching goal of better outcomes and quality of life for patients with thalassemia.

Newborn Screening for Severe Combined Immunodeficiency and T-cell Lymphopenia in California, 2010-2017.

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

Follow-up status during the first 5 years of life for metabolic disorders on the federal Recommended Uniform Screening Panel.

PURPOSE: To investigate the 5-year follow-up status for newborns diagnosed with metabolic disorders designated as "primary disorders" on the federal Recommended Uniform Screening Panel (RUSP). METHODS: Follow-up status and demographic characteristics are described for 426 newborns diagnosed with one of 20 primary metabolic disorders on the RUSP between 2005 and 2009. Newborn screening program data were linked to birth certificate data. Follow-up status is described for each year through age 5 and by disorder type. Maternal characteristics of those who stayed in active care were compared with those who did not. RESULTS: Of 426 diagnosed newborns, by the end of 5 years of follow-up 55.2% stayed in active care, 20.4% became lost to follow-up, 8.7% moved out of state, 6.3% were determined to require no further follow-up, 4.7% refused follow-up, and 4.7% died. Among the initial group of disorders with more than 10 diagnosed cases, phenylketonuria (90%) had the highest percentage of patients still in active care after 5 years. Patients in active care had similar characteristics to patients not in active care when maternal age, race/ethnicity, completed education years, and expected source of payment for delivery were compared. CONCLUSION: Staying in active care may associate with disorder type but not maternal characteristics.

Genomic sequencing in cystic fibrosis newborn screening: what works best, two-tier predefined CFTR mutation panels or second-tier CFTR panel followed by third-tier sequencing?

PurposeThe purpose of this study was to model the performance of several known two-tier, predefined mutation panels and three-tier algorithms for cystic fibrosis (CF) screening utilizing the ethnically diverse California population.MethodsThe cystic fibrosis transmembrane conductance regulator (CFTR) mutations identified among the 317 CF cases in California screened between 12 August 2008 and 18 December 2012 were used to compare the expected CF detection rates for several two- and three-tier screening approaches, including the current California approach, which consists of a population-specific 40-mutation panel followed by third-tier sequencing when indicated.ResultsThe data show that the strategy of using third-tier sequencing improves CF detection following an initial elevated immunoreactive trypsinogen and detection of only one mutation on a second-tier panel.ConclusionIn a diverse population, the use of a second-tier panel followed by third-tier CFTR gene sequencing provides a better detection rate for CF, compared with the use of a second-tier approach alone, and is an effective way to minimize the referrals of CF carriers for sweat testing. Restricting screening to a second-tier testing to predefined mutation panels, even broad ones, results in some missed CF cases and demonstrates the limited utility of this approach in states that have diverse multiethnic populations.

Emergency department utilization by Californians with sickle cell disease, 2005-2014.

BACKGROUND: Clinical care for children and adults living with sickle cell disease (SCD) is often provided in the emergency department (ED). Population-based surveillance data can be used to describe the ED utilization patterns of this patient population. PROCEDURE: A cohort of pediatric and adult California patients with SCD was identified from multiple data sources, and 10 years (2005-2014) of their treat-and-release ED utilization data were analyzed. RESULTS: Among a cohort of 4,636 patients with SCD, 4,100 (88%) had one or more treat-and-release ED visits. There were 2.1 mean annual visits per person for the cohort (median 0.7; range 0-185). In a single year (2005), 53% had 0 treat-and-release ED visits, 35% had 1-3 visits, 9% had 4-10 visits, and 3% had 11 or more visits; this highest utilization group accounted for 45% of all patients' ED visits. ED utilization in this cohort was highest among young adults and also higher among older adults than pediatric patients. CONCLUSION: The majority of identified patients in each of the 10 years did not go to the ED, but nearly all had one or more such visits over the full span of time. This study highlights the power and utility of a multisource longitudinal data collection effort for SCD. Further study of the segment of the population with highest ED utilization may highlight areas where changes in healthcare and health policy could improve and extend the lives of patients with SCD.

A framework for assessing outcomes from newborn screening: on the road to measuring its promise.

UNLABELLED: Newborn screening (NBS) is intended to identify congenital conditions prior to the onset of symptoms in order to provide early intervention that leads to improved outcomes. NBS is a public health success, providing reduction in mortality and improved developmental outcomes for screened conditions. However, it is less clear to what extent newborn screening achieves the long-term goals relating to improved health, growth, development and function. We propose a framework for assessing outcomes for the health and well-being of children identified through NBS programs. The framework proposed here, and this manuscript, were approved for publication by the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children (ACHDNC). This framework can be applied to each screened condition within the Recommended Uniform Screening Panel (RUSP), recognizing that the data elements and measures will vary by condition. As an example, we applied the framework to sickle cell disease and phenylketonuria (PKU), two diverse conditions with different outcome measures and potential sources of data. Widespread and consistent application of this framework across state NBS and child health systems is envisioned as useful to standardize approaches to assessment of outcomes and for continuous improvement of the NBS and child health systems. SIGNIFICANCE: Successful interventions for newborn screening conditions have been a driving force for public health newborn screening for over fifty years. Organizing interventions and outcome measures into a standard framework to systematically assess outcomes has not yet come into practice. This paper presents a customizable outcomes framework for organizing measures for newborn screening condition-specific health outcomes, and an approach to identifying sources and challenges to populating those measures.

Defining Sickle Cell Disease Mortality Using a Population-Based Surveillance System, 2004 through 2008.

OBJECTIVE: Population-based surveillance data from California and Georgia for years 2004 through 2008 were linked to state death record files to determine the all-cause death rate among 12,143 patients identified with sickle cell disease (SCD). METHODS: All-cause death rates, by age, among these SCD patients were compared with all-cause death rates among both African Americans and the total population in the two states. All-cause death rates were also compared with death rates for SCD derived from publicly available death records: the compressed mortality files and multiple cause of death files. RESULTS: Of 12,143 patients identified with SCD, 615 patients died. The all-cause mortality rate for the SCD population was lower than the all-cause mortality rate among African Americans and similar to the total population all-cause mortality rates from birth through age 4 years, but the rate was higher among those with SCD than both the African American and total population rates from ages 5 through 74 years. The count of deceased patients identified by using population-based surveillance data (n=615) was more than twice as high as the count identified in compressed mortality files using SCD as the underlying cause of death alone (n=297). CONCLUSION: Accurate assessment of all-cause mortality and age at death requires long-term surveillance via population-based registries of patients with accurately diagnosed SCD.

Damaged goods?: an empirical cohort study of blood specimens collected 12 to 23 hours after birth in newborn screening in California.

PURPOSE: The current Clinical and Laboratory Standards Institute standard recommends blood collection from 24 to 48 hours after birth for newborn genetic disorder screening. We used California population-level data to determine whether early specimens (collected from 12 to 23 hours) would also be considered satisfactory based on screening performance. METHODS: Screening data from California Genetic Disease Screening Program were analyzed for false-negative and false-positive rates in four disease categories: metabolic disorders detectable by tandem mass spectrometry (MS/MS); congenital adrenal hyperplasia (CAH); congenital hypothyroidism (CH); and initial immune reactive trypsinogen (IRT) for cystic fibrosis (CF). We compared the rates between the early-collection group (12 to 23 hours) and the standard-collection group (24 to 48 hours). RESULTS: No significant difference of false-negative rate was detected between the two collection-timing groups. Early specimens had a significantly higher false-positive rate for CH (0.10 vs. 0.01%) and IRT (1.85 vs. 1.54%) but a lower false-positive rate for MSMS metabolic disorders (0.11 vs. 0.18%) and CAH (0.10 vs. 0.14%). CONCLUSION: Newborn specimens collected after 12 hours provided satisfactory screening performance. A policy allowing earlier collection could improve timeliness of reporting screening results.

Newborn Screening for Cystic Fibrosis in California.

OBJECTIVES: This article describes the methods used and the program performance results for the first 5 years of newborn screening for cystic fibrosis (CF) in California. METHODS: From July 16, 2007, to June 30, 2012, a total of 2,573,293 newborns were screened for CF by using a 3-step model: (1) measuring immunoreactive trypsinogen in all dried blood spot specimens; (2) testing 28 to 40 selected cystic fibrosis transmembrane conductance regulator (CFTR) mutations in specimens with immunoreactive trypsinogen values ≥62 ng/mL (top 1.6%); and (3) performing DNA sequencing on specimens found to have only 1 mutation in step 2. Infants with ≥2 mutations/variants were referred to CF care centers for diagnostic evaluation and follow-up. Infants with 1 mutation were considered carriers and their parents offered telephone genetic counseling. RESULTS: Overall, 345 CF cases, 533 CFTR-related metabolic syndrome cases, and 1617 carriers were detected; 28 cases of CF were missed. Of the 345 CF cases, 20 (5.8%) infants were initially assessed as having CFTR-related metabolic syndrome, and their CF diagnosis occurred after age 6 months (median follow-up: 4.5 years). Program sensitivity was 92%, and the positive predictive value was 34%. CF prevalence was 1 in 6899 births. A total of 303 CFTR mutations were identified, including 78 novel variants. The median age at referral to a CF care center was 34 days (18 and 37 days for step 2 and 3 screening test-positive infants, respectively). CONCLUSIONS: The 3-step model had high detection and low false-positive levels in this diverse population.

Undiagnosed metabolic dysfunction and sudden infant death syndrome--a case-control study.

BACKGROUND: Decades of research has yielded few clues about causes of sudden infant death syndrome (SIDS). While some studies have shown a link to inborn errors of metabolism (IEMs), few have examined the link in a large population-based sample. This population-based case-control study assessed the association between undiagnosed IEMs and SIDS. METHODS: Children born in California during 2005-08 who died from SIDS were obtained from death records and linked to the newborn screening, birth certificate, and hospital discharge databases. Individuals with known chromosomal and neural tube defects, genetic disorders, and non-singleton births were excluded. Five controls were matched to each case on tandem mass spectrometry testing date and lab code. Rates of undiagnosed IEMs were compared between cases and controls using conditional logistic regression adjusting for known confounding factors. RESULTS: After adjusting for known confounding factors, SIDS cases had similar risk of having IEMs as controls (adjusted hazard ratio [HR] 1.3, 95% confidence interval [CI] 0.3, 5.5). Infants who were male, Black, and born preterm had higher risk of SIDS with the highest risk observed for those born preterm [adjusted HR = 1.7, 95% CI 1.3, 2.2]. Younger maternal age at delivery, mother being born in the US, parity after current birth >3, and delayed prenatal care were also significantly associated with higher risk of SIDS. CONCLUSIONS: While many maternal and infant factors are associated with an increased risk of SIDS, there is no evidence that undiagnosed IEMs are associated with increased risk.

State-based surveillance for selected hemoglobinopathies.

PURPOSE: The lack of an ongoing surveillance system for hemoglobinopathies in the United States impedes the ability of public health organizations to identify individuals with these conditions, monitor their health-care utilization and clinical outcomes, and understand the effect these conditions have on the health-care system. This article describes the results of a pilot program that supported the development of the infrastructure and data collection methods for a state-based surveillance system for selected hemoglobinopathies. METHODS: The system was designed to identify and gather information on all people living with a hemoglobinopathy diagnosis (sickle cell diseases or thalassemias) in the participating states during 2004-2008. Novel, three-level case definitions were developed, and multiple data sets were used to collect information. RESULTS: In total, 31,144 individuals who had a hemoglobinopathy diagnosis during the study period were identified in California; 39,633 in Florida; 20,815 in Georgia; 12,680 in Michigan; 34,853 in New York, and 8,696 in North Carolina. CONCLUSION: This approach provides a possible model for the development of state-based hemoglobinopathy surveillance systems.

Population based surveillance in sickle cell disease: methods, findings and implications from the California registry and surveillance system in hemoglobinopathies project (RuSH).

BACKGROUND: There are no population-based surveillance systems to determine prevalence, impact or outcomes in sickle cell disease (SCD). Estimates of the SCD population in California range broadly from 4,500 to 7,000, and little is known about their health status, health care utilization or health outcomes. A surveillance strategy was implemented using diverse data sources to develop a multi-dimensional, state-based surveillance system for SCD that includes adults and children and describes utilization, treatment and outcomes. PROCEDURE: Data from California newborn screening, inpatient and emergency room records, Medi-Cal/Medicaid claims and two SCD special care centers were collected for 2004-2008. A multi-step, iterative linkage process was used to link and de-duplicate these data sources, and case definitions were used to categorize cases. RESULTS: After linking and de-duplicating, there were 1,975 confirmed cases of SCD, 3,159 probable cases as well as 8,024 possible cases. Among individual data sources, newborn screening and data from clinics contributed the greatest number of unique cases to the total. Select analyses of utilization and treatments for the population are described. CONCLUSIONS: Using linked existing data sources, an estimate of the statewide count of the SCD population is possible. The approach can be used to create an in-depth health status profile of the affected population by aggregating utilization, treatment, and outcomes data including mortality and morbidity information. This effort sets the stage for development of an on-going, state-based surveillance system.

Infants suspected to have very-long chain acyl-CoA dehydrogenase deficiency from newborn screening.

Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid oxidation disorder with widely varying presentations that has presented a significant challenge to newborn screening (NBS). The Western States Regional Genetics Services Collaborative developed a workgroup to study infants with NBS positive for VLCADD. We performed retrospective analysis of newborns with elevated C14:1-acylcarnitine on NBS in California, Oregon, Washington, and Hawai'i including available confirmatory testing and clinical information. Overall, from 2,802,504 children screened, there were 242 cases screen-positive for VLCADD. There were 34 symptomatic true positive cases, 18 asymptomatic true positives, 112 false positives, 55 heterozygotes, 11 lost to follow-up, and 12 other disorders. One in 11,581 newborns had an abnormal NBS for suspected VLCADD. Comparison of analytes and analyte ratios from the NBS demonstrated statistically significant differences between true positive and false positive groups for C14:1, C14, C14:1/C2, and C14:1/C16. The positive predictive value for all true positive cases was 94%, 54%, and 23% when C14:1 was ≥2.0 µM, ≥1.0 µM, and ≥0.7 µM, respectively. Sequential post-analytical analysis could reduce the referral rate in 25.8% of cases. This study is the largest reported follow-up of infants with NBS screen-positive results for suspected VLCADD and demonstrates the necessity of developing comprehensive and consistent long-term follow-up NBS systems. Application of clinical information revealed differences between symptomatic and asymptomatic children with VLCADD. Comparison of NBS analytes and analyte ratios may be valuable in developing more effective diagnostic algorithms.

Developing a public health-tracking system for follow-up of newborn screening metabolic conditions: a four-state pilot project structure and initial findings.

PURPOSE: The aim of this study was to describe the methods, cases, and initial results of a pilot project using existing public health data collection programs (birth defect surveillance or newborn screening) to conduct long-term follow-up of children with metabolic disorders. METHODS: California, Iowa, New York, and Utah expanded birth defect surveillance or newborn screening programs to collect long-term follow-up data on 19 metabolic disorders. Data elements to monitor health status and services delivered were identified, and record abstraction and data linkages were conducted. Children were followed up through to the age of 3 years. RESULTS: A total of 261 metabolic cases were diagnosed in 1,343,696 live births (19.4 cases/100,000; 95% confidence interval = 17.1-21.8). Four deaths were identified. Children with fatty acid oxidation disorders had a higher percentage of health service encounters compared with children with other disorders of at least one health service encounter (hospitalization, emergency room, metabolic clinic, genetic service provider, or social worker) except for hospitalizations; children with organic acid disorders had a higher percentage of at least one hospitalization during their third year of life than children with other disorders. CONCLUSION: Existing public health data programs can be leveraged to conduct population-based newborn screening long-term follow-up. This approach is flexible according to state needs and resources. These data will enable the states in assessing health burden, assuring access to services, and supporting policy development.

Analysis of cases of 3-methylcrotonyl CoA carboxylase deficiency (3-MCCD) in the California newborn screening program reported in the state database.

BACKGROUND AND METHODS: There are considerable uncertainty and debate regarding all aspects of newborn screen-positive cases of 3-methylcrotonyl-CoA carboxylase deficiency (3-MCCD), including diagnostic criteria, clinical spectrum, morbidity, prognosis, and appropriate management. To address some of these questions, we queried data from the California Newborn Screening Program's Screening Information System (SIS) and available scanned laboratory reports on cases of 3-MCCD reported by 15 state contracted metabolic specialty care centers born between July 2005 and December 2010. We evaluated the completeness and utility of the database as a tool for clinical disease characterization. RESULTS: During the study period, 2,959,108 infants were screened and 71 infants were diagnosed with 3-MCCD for an overall incidence of 1:41,676. The availability of diagnostic biochemical laboratory data varied significantly from subject to subject. Using a new case classification based on biochemical severity, we found that 8 of the cases met our criteria for biochemically severe (category 1), 19 cases met our criteria for biochemically mild (category 2) that we suspect to possibly be hypomorphic variants or heterozygote carriers, and 44 cases could not be classified (category 3) as mild or severe based on the data available in SIS. Documentation of the treatment regimens also varied significantly with 49% receiving dietary modification and 44% receiving carnitine. 15% of cases were documented to have experienced at least one of the following symptoms: lethargy, vomiting, irritability, ketosis, poor feeding, or poor tone. The majority of the subjects were completely developmentally age appropriate at their last assessment. CONCLUSIONS: The results suggest that a significant portion of the 3-MCCD "confirmed" cases have a mild biochemical phenotype. Moreover the majority of cases had insufficient data entered to allow for adequate clinical characterization of the cases. These findings raise the concern that a significant number of individuals receiving treatment for 3-MCCD may not have a clinically significant condition. Additionally, the utility of this data system could be improved if centers provided complete confirmatory test results and more specific documentation of clinical outcomes and health/developmental status. Further studies, including a clinical chart review, are necessary to validate the data and further characterize this cohort.