Elucidating the phenotypic variability associated with the polyT tract and TG repeats in CFTR

ABSTRACT Purpose To evaluate the risk and spectrum of phenotypes associated in individuals with one or two of the CFTR T5 haplotype variants (TG11T5, TG12T5 and TG13T5) in the absence of the R117H variant. Methods Individuals who received testing with CFTR NGS results between 2014 and 2019 through Invitae at ordering provider discretion were included. TG-T repeats were detected using a custom-developed haplotype caller. Frequencies of the TG-T5 variants (biallelic or in combination with another CF-causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider (via requisition form) or the individual (during genetic counseling appointments) was examined. Results Among 548,300 individuals, the minor allele frequency of the T5 allele was 4.2% (TG repeat distribution: TG11=68.1%, TG12=29.5%, TG13=2.4%). When present with a CFvar, each of the TG[11-13]T5 variants were significantly enriched in individuals with a “high suspicion” of CF/CFTR-RD (personal/family history of CF/CFTR-RD) compared to those with very “low suspicion” for CF or CFTR-RD (hereditary cancer testing, CFTR not requisitioned). Compared to CFvar/CFvar individuals, TG[11-13]T5/CFvar individuals generally had single organ involvement, milder symptoms, variable expressivity, and reduced penetrance. Discussion Data from this study provides a better understanding of disease risks associated with inheriting TG[11-13]T5 variants and has important implications for reproductive genetic counseling.