Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance. Issue 2 (26th September 2022) - Viall, Sarah
Abstract: Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first‐tier enzyme quantitation and second‐tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non‐A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.