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\begin{document}

\title{Mutation profiling of the F508del CFTR allele using haplotype-resolved
long-read next generation sequencing}



\author[1]{Dario Dilernia}%
\author[1]{Pooneh Amin}%
\author[1]{Julie Flores}%
\author[1]{Arlene Stecenko}%
\author[1]{Eric Sorscher}%
\affil[1]{Emory University}%


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  \date{June 18, 2024}


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\begin{abstract}
Current approaches to characterize the mutational profile of CFTR are
based on targeted mutation analysis (TMA) or whole gene studies derived
from short-read next generation sequencing (NGS). However, these methods
lack phasing capability which, in certain scenarios, can provide
clinically valuable information. In the present work, we performed
near-full length CFTR using Single-Molecule Real-Time Sequencing to
produce haplotype resolved data from F508del homozygous and F508del
compound heterozygous individuals. This approach utilizes target
enrichment of the CFTR gene using biotinylated probes, facilitates
multiplexing samples in the same sequencing run, and utilizes
fully-automated bioinformatics pipelines for error correction and
variant calling. We show a remarkable conservation of F508del haplotype,
consistent with the single gene founder effect, as well as diverse
mutational profiles in non-F508del alleles. By the same method, 105
single nucleotide polymorphisms exhibiting invariant linkage to F508del
CFTR (which better define the founder haplotype) were identified. High
level homology between F508del sequences derived from heterozygotes, and
those obtained from homozygous individuals, demonstrate accuracy of this
method to produce haplotype resolved sequencing. The studies provide a
new diagnostic technology for detailed analysis of complex CFTR alleles
linked to disease severity.%
\end{abstract}%



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