CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

Abstract

Background: There are no predictive factors of evolution of cystic fibrosis (CF) screen positive inconclusive diagnosis subjects (CFSPIDs). Aim: to define the role of the second CFTR variant as a predictive factor of disease evolution in CFSPIDs carrying the D1152H variant. Methods: We retrospectively evaluated clinical characteristics and outcome of CFSPIDs carrying the D1152H variant followed at five Italian CF centers. CFSPIDs were divided in two groups: Group A: compound heterozygous for D1152H and a CF-causing variant; Group B: compound heterozygous for D1152H and a: (i) non CF-causing variant, (ii) variant with varying clinical consequences, or (iii) variant with unknown significance. The variants were classified according to CFTR2 mutation database. Results: We enrolled 43 CFSPIDs with at least one D1152H variant: 28 (65.1%) were classified in the group A, and 15 (34.9%) in the Group B. CFSPIDs of group A had the first IRT significantly higher compared to those of group B (p < 0.05) and had a more severe clinical outcome during the follow-up. At the end of the study period, after a mean follow-up of 40.6 months (range 6–91.6), 4 (9.3%) out of 43 CFSPIDs progressed to CFTR-RD or CF. All these subjects were in the group A. Conclusions: The genetic profile could help predict the risk of disease evolution in CFSPIDs carrying D1152H, revealing the subjects that need a more frequent follow-up.

Outcomes of early repeat sweat testing in infants with cystic fibrosis transmembrane conductance regulator‐related metabolic syndrome/CF screen‐positive, inconclusive diagnosis

“…Repeat testing should be more frequent in the 1st year of life in subjects with one or no CFTR variant, to discharge healthy subjects or healthy carriers, or in subjects with a CF-causing variant in trans with a variant with varying clinical consequences, such as D1152H or (TG) 12T5, to identify CF patients earlier. 10,11,25 However, our study has some limitations: first of all, the small number of subjects which affects power, in particular about the b-IRT comparison analyses and the lack of differences. Furthermore, the random and lack of standardised timing and frequency of ST is also an issue.…”

“…For these reasons, differentiating the timing of the ST could be useful. Repeat testing should be more frequent in the 1st year of life in subjects with one or no CFTR variant, to discharge healthy subjects or healthy carriers, or in subjects with a CF‐causing variant in trans with a variant with varying clinical consequences, such as D1152H or (TG)12T5, to identify CF patients earlier 10,11,25 …”

Lung clearance index in children with cystic fibrosis previously diagnosed with CRMS/CFSPID: A monocentric prospective experience

“…As already reported this is a genetic profile associated with an increased risk of disease evolution, at least in the Italian population. 12,14,35,36 The group of subjects with an inconclusive diagnosis had a lower mean age than the group that progressed to 38 It's known that LCI is a primary outcome more sensitive that FEV 1 for detecting early lung disease. It is less dependent on patient effort, making it suitable for the pediatric population.…”

Addressing Uncertainty: The Emergence of the CRMS/CFSPID Diagnostic Category Following Newborn Screening for Cystic Fibrosis

“…While programs with expanded CFTR sequence analysis have the advantage of promoting equity by detecting mutations in a wider range of racialized groups, the increased ability to detect CFTR variants has been associated with an elevated CRMS/CFSPID detection rate as well [45,46]. Some investigators view this as advantageous, since certain individuals with CRMS/CFSPID have gone on to develop signs and symptoms consistent with CF, yet other investigators have described the detection of such infants as concerning due to the associated parental anxiety and medicalization of children because many "may never develop the disease" [47,[103][104][105]. In fact, reflecting on parental anxiety in the setting of the COVID-19 pandemic, physician Danieli Salinas recalled that "a lot of them contacted us for guidance, asking specifically about CRMS being a pre-existing condition that would put their child at a higher risk of dying from COVID" [106].…”