De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms

Fluri R, Coll-Tané M, Brunet T, Cogne B, Conrad S, Nizon M, Nicita F, Travaglini L, Novelli A, Glissmeyer M, Peterson A, Buchan JG, Serber D, Meier K, Gärtner J, Diegmann S, Pingault V, Attie-Bitach T, Courtin T, Schneider MC, Hung W, Sahai I, O’Grady L, Steindl K, Mehta SG, Depienne C, Heron D, Keren B, Heide S, McKee S, Laccone F, Dyer LM, Melver C, Motter C, Jones WD, Wilson ZT, Vats D, Huß K, Zweier C, Sticht H, Gregor A (2026)

Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1016/j.ajhg.2026.05.012

Abstract

LDB1 encodes transcriptional regulator protein LIM domain-binding protein 1, which plays an important role in neurogenesis. Few C-terminal likely gene-disrupting (LGD) variants have been reported in the literature in individuals with congenital ventriculomegaly. Through international collaboration, we now assembled a cohort of 16 individuals with de novo variants affecting various regions of LDB1. Eleven variants affect either the whole gene or the N-terminal dimerization domain (including gene deletions, as well as nonsense-mediated mRNA decay (NMD)-sensitive LGD and missense variants), and five variants (missense or NMD-escaping LGD variants) affect only the C terminus of LDB1 containing the LIM interaction domain. All individuals showed variable neurodevelopmental phenotypes, including developmental delay and behavioral anomalies. In line with literature reports, individuals harboring C-terminal variants additionally presented with ventriculomegaly, which suggests a potential genotype-phenotype correlation. In accordance, we found diverging pathomechanisms in vitro : N-terminal missense variants disrupt homodimerization of LDB1, likely leading to a loss of function, while C-terminal variants impair interaction with the essential partner LHX2 in a dominant-negative manner. These findings were confirmed in vivo in Drosophila melanogaster . Toxicity of overexpressed human LDB1 in Drosophila was not observed with N-terminal missense variants but was exacerbated by C-terminal variants. Similarly, phenotypes associated with LDB1/chi loss were rescued by overexpression of wild-type LDB1 but not by LDB1 harboring N-terminal missense variants or by C-terminal variants that even worsened phenotypes. In summary, our findings indicate that de novo variants in LDB1 are linked to two overlapping but distinct neurodevelopmental phenotypes based on variant location and propose two separate pathomechanisms underlying LDB1 -related neurodevelopmental disorders.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Essen Germany (DE) Assistance Publique-Hôpitaux de Paris (AP-HP) France (FR) Belfast City Hospital / Ospidéal Chathair Bhéal Feirste United Kingdom (GB) Medizinische Universität Wien Austria (AT) GeneDX United States (USA) (US) Akron Children's Hospital United States (USA) (US) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Kaiser Permanente United States (USA) (US) Klinikum der Universität München (LMU Klinikum) Germany (DE) Inselspital, Universitätsspital Bern Switzerland (CH) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Technische Universität München (TUM) Germany (DE) Université de Nantes France (FR) Ospedale Pediatrico Bambino Gesu Italy (IT) Seattle Children's Hospital United States (USA) (US) University of Washington United States (USA) (US) Universitätsklinikum Göttingen Germany (DE) Hôpital Necker-Enfants malades France (FR) St. Christopher's Hospital for Children United States (USA) (US) Massachusetts General Hospital United States (USA) (US) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Cambridge University Hospitals United Kingdom (GB)

How to cite

APA:

Fluri, R., Coll-Tané, M., Brunet, T., Cogne, B., Conrad, S., Nizon, M.,... Gregor, A. (2026). De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2026.05.012

MLA:

Fluri, Rebecca, et al. "De novo variants in LDB1 are linked to distinct neurodevelopmental phenotypes determined by variant location and differing pathomechanisms." American Journal of Human Genetics (2026).

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