Hydrocephalus

Gene: LDB1

Green List (high evidence)

PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, distinguishing two variant classes with distinct phenotypic and mechanistic consequences. Ventriculomegaly/enlarged ventricles was observed in 9/9 individuals with detailed clinical data who carried C-terminal LID-disrupting (frameshift/nonsense/splice-site) variants, versus only 1/7 individuals with N-terminal LGD or DD-missense variants. Four C-terminal LID-disrupting LGD variants (p.Ser317Argfs21, p.Gln333, p.Glu349Serfs134, p.Arg356Serfs127) and one LID missense variant (p.Thr359Pro) were newly reported, in addition to prior literature reports of 8 C-terminal LGD + 1 missense variant. All these evidence support a genotype-specific association between C-terminal LDB1 variants and hydrocephalus/ventriculomegaly.

C-terminal LID-affecting LDB1 variants abolished LHX2 binding and act dominant-negatively, suppressing wild-type LDB1–LHX2 interaction below expected levels while also showing increased protein stability and nuclear aggregate formation unlike N-terminal variants. This dominant-negative mechanism was also confirmed in vivo, as C-terminal variants worsened viability upon overexpression and failed to rescue (or exacerbated) chi loss-of-function phenotypes in Drosophila, in contrast to N-terminal variants.

This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026).

Created: 16 Aug 2026, 8:18 p.m. | Last Modified: 16 Aug 2026, 8:40 p.m.

Panel Version: 5.18

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
congenital hydrocephalus, MONDO:0016349; neurodevelopmental disorder, MONDO:0700092

Publications

• 42320471

Mode of pathogenicity
Other

Green List (high evidence)

Comment on list classification: There is sufficient evidence to promote this gene to Green at the next GMS panel update - more than 10 unrelated individuals with de novo variants in this gene and ventriculomegaly and/or hydrocephalus.

Created: 12 Dec 2025, 11:35 a.m. | Last Modified: 12 Dec 2025, 11:35 a.m.

Panel Version: 5.5

- Allington et al. 2024 (PMID: 39680505) investigate a cohort of 2697 trios with congenital primary cerebral ventriculomegaly using WES. Eight unrelated individuals identified with de novo variants in LDB1 (7 LOF, 1 predicted damaging missense) - exhibiting perinatally diagnosed cerebral ventriculomegaly, including neurosurgically treated congenital hydrocephalus. Additionally, 5/8 GDD, 3/8 autism, 2/8 delayed gross motor development, 2/8 had congenital heart defects (inc. coarctation, PDA), 2/8 camptodactyly.

Additional case was identified from GeneMatcher with a de novo frameshift variants in LDB1. Phenotypes include severe ventriculomegaly, absence of well formed gyri, severe limb contractures and camptodactyly. Search of Decipher/DDD also revealed 4 pathogenic de novo variants in LDB1 and associated binding partners in individuals congenital ventriculomegaly.

- Torene et al. 2023 (PMID: 38091987) identified three individuals with protein truncating variants. Two individuals with de novo variants both had ventriculomegaly, hypotonia, GDD, craniofacial abnormalities. The third individual inherited the variants from an asymptomatic mother, and displayed developmental delay, hypotonia, congenital heart defects and a small hypoplastic hippocampi but did not have ventriculomegaly or craniofacial anomalies.

- Jin et al. 2020 (PMID: 33077954) also report an individual with a de novo LOF variant in this gene who had congenital hydrocephalus but details on this case are otherwise limited.
Sources: Literature

Created: 12 Dec 2025, 11:32 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Congenital hydrocephalus, MONDO:0016349

Publications

• 39680505
• 38091987
• 33077954