Lymphangioleiomyomatosis (LAM) diagnosis is categorized as one of two subtypes: Tuberous sclerosis complex-associated LAM (TSC-LAM) or sporadic LAM (S-LAM). Differentiating LAM subtypes is critical as it informs treatment strategy. S-LAM patients often experience faster disease progression and increased severity, and not all LAM patients respond to mTOR inhibition therapy. Although the genetic variant(s) causing LAM are commonly in TSC2, the frequency and contributions of other somatic mutations to disease manifestation remain unknown. And S-LAM is considered distinct from TSC-LAM, not the result of systemic mosaicism. The objective of this study is to apply PacBio HiFi long read sequencing to identify mutations in lung tissue samples from cases of S-LAM. HiFi sequencing uses long read lengths and base-pair resolution to generate complete genome assemblies. We will detect variants not captured by conventional sequencing methods including large deletions or insertions, repeat expansions, translocations, and phasing to distinguish maternal and paternal haplotypes. HiFi sequencing will be readily applied to pre-existing or prospectively collected tissue samples accessed through the National Disease Research Interchange. Completion of this pilot study will identify genomic signatures not previously captured by conventional sequencing methods to gain a deeper knowledge about LAM disease etiology and inform innovative mechanisms for therapeutic targeting. The proposed research serves as the foundation for a new line of research for the junior faculty applicant who is new to LAM research but has unique access world experts in clinical application of HiFi technology to identify genomic underpinnings of unsolved rare disease.

2024-09-01

2025-09-01