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De novo variants disrupt an LDB1-regulated transcriptional network in congenital ventriculomegaly
Garrett Allington1,2,3,4, Neel H Mehta2, Evan Dennis2
1Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, USA.
Insights
Researchers identified mutations in the LDB1 gene as a significant cause of congenital hydrocephalus, a common pediatric brain disorder. This finding reveals LDB1
Area of Science:
- Genetics and Genomics
- Neuroscience
- Developmental Biology
Background:
- Congenital hydrocephalus, marked by cerebral ventriculomegaly, is a frequent and poorly understood pediatric neurosurgical condition.
- Genetic factors underlying ventriculomegaly are not fully elucidated, necessitating large-scale studies to identify causative genes.
Purpose of the Study:
- To identify novel genetic variants associated with congenital hydrocephalus and ventriculomegaly.
- To investigate the role of the LDB1 gene and its regulatory network in human brain development and morphogenesis.
Main Methods:
- Exome-wide analysis of 2697 parent-proband trios with cerebral ventriculomegaly.
- Identification and characterization of de novo variants, particularly loss-of-function mutations in LDB1.
- Integrative multiomic analyses to determine LDB1's function in neuroprogenitors and its interaction with LIM-homeodomain proteins.
Main Results:
- A highly significant enrichment of protein-altering de novo variants in the LDB1 gene was found in the ventriculomegaly cohort (P = 1.11 × 10-15).
- Loss-of-function variants in LDB1 were identified in eight patients, leading to truncated protein and associated developmental delay and dysmorphic features.
- LDB1 was confirmed as a key transcriptional regulator in ventricular neuroprogenitors, interacting with SMARCC1 and ARID1B, which also showed significant variant burden.
Conclusions:
- LDB1 is identified as a novel gene implicated in neurodevelopmental disorders, specifically congenital hydrocephalus.
- Disruption of LDB1 function impairs human brain morphogenesis, highlighting the critical role of LDB1-regulated transcriptional programs.
- The study underscores the importance of LIM-homeodomain-containing genes in brain development and the etiology of ventriculomegaly.
Abstract:
Congenital hydrocephalus, characterized by cerebral ventriculomegaly, is among the most common and least understood paediatric neurosurgical disorders. We have identified, in the largest assembled cerebral ventriculomegaly cohort (2697 parent-proband trios), an exome-wide significant enrichment of protein-altering de novo variants in LDB1 (P = 1.11 × 10-15). Eight unrelated patients with ventriculomegaly, developmental delay and dysmorphic features harboured loss-of-function de novo variants that truncate carboxy-terminal LIM interaction domain of LDB1, which regulates assembly of LIM homeodomain-containing transcriptional modulators. Integrative multiomic analyses suggest that LDB1 is a key transcriptional regulator in ventricular neuroprogenitors through its binding to LIM-homeodomain proteins, including SMARCC1 and ARID1B. Indeed, LIM-homeodomain-containing genes carry a disproportionate burden of protein-damaging de novo variants in our cohort, with SMARCC1 (P = 5.83 × 10-9) and ARID1B (P = 1.80 × 10-17) surpassing exome-wide significance thresholds. These data identify LBD1 as a novel neurodevelopmental disorder gene and suggest that an LDB1-regulated transcriptional programme is essential for human brain morphogenesis.
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