Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.

Lu Liu; David Wu; Amit Manhas; Chikage Noishiki; Dipti Tripathi; Safa Sadat; Nike Bharucha; Ioannis Karakikes; Karim Sallam; Nazish Sayed

doi:10.1016/j.scr.2026.104086

PubMed · 42648117

Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.

Lu Liu·David Wu·Amit Manhas·Chikage Noishiki·Dipti Tripathi·Safa Sadat·Nike Bharucha·Ioannis Karakikes·Karim Sallam·Nazish Sayed

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Abstract

Variants of uncertain significance (VUS) in the LMNA gene represent a major challenge in clinical genetics, as insufficient functional evidence limits their interpretation and clinical decision-making in laminopathies, including dilated cardiomyopathy (DCM). Here, we generated two isogenic induced pluripotent stem cell (iPSC) lines carrying homozygous LMNA variants, c.293A > G (p.Glu98Gly) and c.439G > A (p.Ala147Thr) by prime editing of a healthy donor iPSC line. Both variants are located within Coil 1B domain of lamin A. The edited iPSC lines retain normal morphology, pluripotency, genomic integrity, and trilineage differentiation capacity, providing a valuable platform for functional characterization and potential clinical reclassification of LMNA VUS.

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Humans Induced Pluripotent Stem Cells Lamin Type A Homozygote Cell Line Cardiomyopathies Cell Differentiation Cardiomyopathy, Dilated Induced pluripotent stem cells LMNA Pluripotency Variants of uncertain significance Journal Article

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Lu Liu, David Wu, Amit Manhas, Chikage Noishiki, Dipti Tripathi, Safa Sadat, Nike Bharucha, Ioannis Karakikes, Karim Sallam, Nazish Sayed. 2026-08-22. Generation of two homozygous iPSC lines carrying variants of uncertain significance in LMNA associated with cardiomyopathy.. https://doi.org/10.1016/j.scr.2026.104086

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