De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly

Garrett Allington; Neel H Mehta; Evan Dennis; Kedous Y Mekbib; Benjamin Reeves; Emre Kiziltug; Shuang Chen; Shujuan Zhao; Phan Q Duy; Maha Saleh; Lee C Ang; Baojian Fan; Carol Nelson-Williams; Andrés Moreno-de-Luca; Shozeb Haider; Richard P Lifton; Seth L Alper; Stephen McGee; Sheng Chih Jin; Kristopher T Kahle

doi:10.1093/brain/awae395

De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly

Brain. 2024 Dec 16:awae395. doi: 10.1093/brain/awae395. Online ahead of print.

Authors

Garrett Allington^{1

2

3

4}, Neel H Mehta², Evan Dennis², Kedous Y Mekbib^{2

3}, Benjamin Reeves³, Emre Kiziltug^{2

3}, Shuang Chen⁵, Shujuan Zhao⁶, Phan Q Duy^{7

8

9}, Maha Saleh¹⁰, Lee C Ang¹¹, Baojian Fan², Carol Nelson-Williams¹², Andrés Moreno-de-Luca¹³, Shozeb Haider⁵, Richard P Lifton¹⁴, Seth L Alper^{15

16

17}, Stephen McGee¹⁸, Sheng Chih Jin^{6

19}, Kristopher T Kahle^{2

3

17

20

21

22

23

24

25}

Affiliations

¹ Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
² Department of Neurosurgery, Massachusetts General Hospital & Harvard Medical School, Boston, MA 02114, USA.
³ Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06510, USA.
⁴ Department of Neurology, New York Presbyterian Hospital & Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
⁵ School of Pharmacy, University College London, London WC1E 6BT, UK.
⁶ Department of Genetics, School of Medicine, Washington University, St. Louis, MO 63110, USA.
⁷ Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁸ Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
⁹ Center for Brain Immunology and Glia, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
¹⁰ Clinical Genetics, Department of Pediatrics, London Health Sciences Centre, London, Ontario N6A 5W9, Canada.
¹¹ Department of Pathology, London Health Sciences Centre and Western University, London, Ontario N6A 5C1, Canada.
¹² Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA.
¹³ Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, ON K7L 2V7, Canada.
¹⁴ Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY 10065, USA.
¹⁵ Division of Nephrology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
¹⁶ Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
¹⁷ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁸ GeneDx, Gaithersburg, MD 20877, USA.
¹⁹ Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA.
²⁰ Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
²¹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
²² Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA.
²³ Department of Pediatrics, Boston Children's Hospital, Boston, MA 02115, USA.
²⁴ Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
²⁵ Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA 02114, USA.

PMID: 39680505
DOI: 10.1093/brain/awae395

Abstract

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly (CV), is among the most common and least understood pediatric neurosurgical disorders. We have identified in the largest-assembled CV cohort (>2,697 parent-proband trios) an exome-wide significant enrichment of protein-altering de novo variants (DNVs) in LDB1 (p = 1.11 x 10-15). Eight unrelated patients with ventriculomegaly, developmental delay, and dysmorphic features harbored loss-of-function DNVs that truncate LDB1's carboxy-terminal LIM interaction domain, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through it's binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging DNVs in our cohort, with SMARCC1 (p = 5.83 x 10-9) and ARID1B (p = 1.80 x 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest an LDB1-regulated transcriptional program is essential for human brain morphogenesis.

Keywords: de novo variants; LDB1; brain development; hydrocephalus; neural stem cells; structural brain disorders.

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