Molecular testing in newborn screening: VUS burden among true positives and secondary reproductive limitations via expanded carrier screening panels.

PURPOSE: Expanded carrier screening (ECS) gene panels have several limitations, including variable content, current knowledge of disease-causing variants, and differing reporting policies. This study evaluated if the disease-associated variants identified in affected neonates who screened positive by California newborn screening (NBS) for an inherited metabolic disorder (IMD) by tandem mass spectrometry (MS/MS) would likely be reported by ECS gene panels. METHODS: Retrospective review of neonates referred by the California Department of Public Health for a positive NBS by multianalyte MS/MS from January 1, 2020 through June 30, 2021. RESULTS: One hundred thirty-six neonates screened positive for ≥1 NBS MS/MS indication. Nineteen neonates (14%) were ultimately diagnosed with an IMD, all of whom had abnormal biochemical testing. Eighteen of the 19 underwent molecular testing; 10 (56%) neonates had ≥1 variants of uncertain significance, 9 of whom were of non-White ancestry. ECS panels would have been negative for 56% (20/36) of parents with an affected neonate, 85% (17/20) of whom were of non-White ancestry. CONCLUSION: The number of variants of uncertain significance identified in this cohort highlights the need for more diversified variant databases. Due in part to the lack of diversity in currently sequenced populations, genomic sequencing cannot replace biochemical testing for the diagnosis of an IMD.

Frequency of epistaxis and telangiectasia in patients with hereditary hemorrhagic telangiectasia (HHT) in comparison with the general population: Curaçao diagnostic criteria revisited.

PURPOSE: The Curaçao criteria are well-established diagnostic criteria for hereditary hemorrhagic telangiectasia (HHT), but they lack details regarding a predictive presentation of epistaxis and telangiectasias. This study collects and compares data in HHT and population cohorts to inform the application of these criteria. METHODS: In-person interviews regarding epistaxis and targeted examination for telangiectases in a general population cohort (n = 204) and an HHT cohort (n = 432) were conducted. RESULTS: Frequency of epistaxis, rather than intensity or duration, was the best discriminator of HHT. A cutoff of ≥4 nosebleeds per year alone yielded a diagnostic sensitivity of 97%, and specificity of 84%. The mean number of telangiectases at the sites investigated was 0.4 in the general population cohort and 26.5 in the HHT cohort. The most distinctive sites for telangiectases in HHT were lips and palmar fingers, whereas telangiectases of the face and dorsum of the hand were comparable in both cohorts. CONCLUSION: We propose that the Curaçao criteria be modified to include the following cutoffs: (1) epistaxis frequency of ≥4 nosebleeds per year and (2) telangiectasia count of at least 2 in characteristic locations (palmar aspect of fingers, lips, and oral cavity), and that cutaneous telangiectases at other sites not be considered relevant for diagnostic purposes.