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

Abstract

Biallelic pathogenic variants in CFTR manifest as cystic fibrosis (CF) or other CFTR‐related disorders (CFTR‐RDs). The 5T allele, causing alternative splicing and reduced protein activity, is modulated by the adjacent TG repeat element, though previous data have been limited to small, selective cohorts. Here, the risk and spectrum of phenotypes associated with the CFTR TG‐T5 haplotype variants (TG11T5, TG12T5, and TG13T5) in the absence of the p.Arg117His variant are evaluated. Individuals who received physician‐ordered next‐generation sequencing of CFTR were included. TG[11‐13]T5 variant frequencies (biallelic or with another CF‐causing variant [CFvar]) were calculated. Clinical information reported by the ordering provider or the individual was examined. Among 548,300 individuals, the T5 minor allele frequency (MAF) was 4.2% (TG repeat distribution: TG11 = 68.1%, TG12 = 29.5%, TG13 = 2.4%). When present with a CFvar, each TG[11‐13]T5 variant was significantly enriched in individuals with a high suspicion of CF or CFTR‐RD (personal/family history of CF/CFTR‐RD) compared to those with a low suspicion for CF or CFTR‐RD (hereditary cancer screening, CFTR not requisitioned). Compared to CFvar/CFvar individuals, those with TG[11‐13]T5/CFvar generally had single‐organ involvement, milder symptoms, variable expressivity, and reduced penetrance. These data improve our understanding of disease risks associated with TG[11‐13]T5 variants and have important implications for reproductive genetic counseling.

Carrier screening in the Mexican Jewish community using a pan-ethnic expanded carrier screening NGS panel

“…32,33 This variable clinical presentation associated with the 5T variant depends greatly on the number of TG repeats also present on the same allele. 34 Long-term studies on patients heterozygous for these variants are needed to better elucidate their risk for abnormal phenotypes.…”

Scalable detection of technically challenging variants through modified next‐generation sequencing

“…CF is an autosomal recessive disorder caused by pathogenic variants in the CFTR gene, which is also associated with CF‐related conditions such as pancreatitis and male infertility. Low‐complexity poly‐T and TG repeats within intron 9 of the CFTR gene can alter splicing of CFTR transcripts, and specific combinations of these repeats with other variants affect clinical manifestation of CF‐related disorders (Nykamp et al, 2021 ). Most individuals have poly‐T genotypes consisting of 5, 7, or 9 Ts, and the presence of 5 Ts is known to disrupt the function of CFTR .…”

Genetic counseling access and service delivery in New York State is variable for parents of infants with complex CFTR genotypes conferring uncertain phenotypes

“…With a reported allele frequency of 4.2%, 5T is quite common in the general population. Nykamp et al found 5T to be enriched in persons tested for a CF‐related indication (e.g., congenital bilateral absence of the vas deferens or chronic sinopulmonary issues) when compared to persons screened for non‐CF indications, such as routine carrier screening 30 . The penetrance of 5T is known to be impacted by an increasing number of linked TG repeats 31 .…”

“…routine carrier screening. 30 The penetrance of 5T is known to be impacted by an increasing number of linked TG repeats. 31 The most common VCC in our cohort was 5T-12TG.…”