Rare biallelic loss-of-function variants in the <i>LRRK2</i> kinase cause interstitial lung disease

Kalayci T, Wikenheiser-Brokamp KA, Gomes S, Rawat E, Peljto A, Cheung A, Citak S, Vayvada M, Montero-Fernandez MA, Mogulkoc N, Okumus NG, Suer I, Kitzmiller J, Na C, Li X, Bell S, Cook KCS, Abu-Remaileh M, Schwartz DA, Uyguner ZO, Whitsett JA, Alessi DR, Zimprich A, Zacharias WJ, Sammler E.

· 2026-05-19

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Summary We report that biallelic LRRK2 loss-of-function (LoF) causes a Mendelian form of interstitial lung disease characterized by alveolar epithelial cell dysfunction and lung fibrosis in two brothers with a homozygous nonsense variant. Integrated clinical, imaging, histopathological, and biomarker analyses showed absent LRRK2 protein, reduced Rab10 phosphorylation, impaired alveolar type 2 cell function, and disrupted surfactant homeostasis. Consistent with a recessive genetic disorder, heterozygous LoF carriers have not been reported to have a lung phenotype. Additional biallelic LRRK2 LoF cases were identified in ILD cohorts, linking LRRK2 LoF to lung disease, in contrast to heterozygous activating missense variants that cause Parkinson’s disease (PD).

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