Abstract Rationale CFTR-Related Metabolic Syndrome (CRMS) occurs when an infant’s cystic fibrosis (CF) newborn screen is abnormal, but the diagnostic resolution to CF or carrier remains inconclusive. This uncertainty results from non-diagnostic sweat chloride concentration (Cl-) or CFTR genotype with variants not clearly disease-causing, often including a variant of varying clinical consequence (VVCC) that confers reduced penetrance for CF. The majority of children with CRMS remain healthy but 10-30% convert to CF. Risk of conversion is increased with the presence of one CF-causing CFTR variant, but other predictors are unknown. Objective To determine the likelihood of CRMS to CF conversion for specific VVCCs in children with CRMS and reason for CF conversion. Methods We performed a systematic review of published cases of children with CRMS with reported genotypes. We evaluated all cases with at least one VVCC to assess the frequency at which the variant occurs in individuals with a persistent CRMS designation versus those who convert to CF, as well as the reason for conversion. Results We identified 23 papers that included CFTR genotype information on 536 unique children with CRMS. Of these, 491 had at least one variant of unclear phenotypic significance, with 240 having one CF-causing variant and at least one VVCC. In this group, 10 CFTR VVCCs appeared 3 or more times, and we show the likelihood of probability to convert to CF compared to the frequency of the variant (Figure 1). Of the children with CRMS, 111 converted to CF. Elevated sweat Cl- (≥60 mmol/L) was the most common reason for conversion. Fifty-nine percent of children converted from CRMS to CF with an isolated elevated sweat chloride test (asymptomatic or unknown symptoms), and an additional 10% had an elevated sweat chloride test and symptoms. Of children who converted, 30% converted from CRMS to CF because of clinical symptoms without an elevated sweat chloride test. Conclusions This is the largest cohort of children with CRMS in the literature, and the first to examine distinct VVCCs with their associated risks and clinical rational for conversion. This can help illuminate the penetrance and expressivity of specific VVCCs, which do not have equal risk for conversion from CRMS to CF. With increased knowledge about individual VVCCs, parents can be given more specific information about their child’s risk of converting to CF, which in turn may impact decision-making regarding the inclusion of specific VVCCs in genetic panels for CF newborn screening. This abstract is funded by: Cystic Fibrosis Foundation
Wyatt et al. (Fri,) studied this question.