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| Hydrocephalus v5.18 | LDB1 |
Achchuthan Shanmugasundram changed review comment from: 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.; to: 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). |
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| Hydrocephalus v5.18 | LDB1 | Achchuthan Shanmugasundram Phenotypes for gene: LDB1 were changed from Congenital hydrocephalus, MONDO:0016349 to congenital hydrocephalus, MONDO:0016349; neurodevelopmental disorder, MONDO:0700092 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.17 | LDB1 | Achchuthan Shanmugasundram Publications for gene: LDB1 were set to 39680505; 38091987; 33077954 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.16 | LDB1 | Achchuthan Shanmugasundram Mode of pathogenicity for gene: LDB1 was changed from None to Other | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.15 | LDB1 | Achchuthan Shanmugasundram reviewed gene: LDB1: Rating: GREEN; Mode of pathogenicity: Other; Publications: 42320471; Phenotypes: congenital hydrocephalus, MONDO:0016349, neurodevelopmental disorder, MONDO:0700092; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.7 | LDB1 | Achchuthan Shanmugasundram Tag gene-checked tag was added to gene: LDB1. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.5 | LDB1 | Arina Puzriakova Classified gene: LDB1 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.5 | LDB1 | Arina Puzriakova Added comment: 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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.5 | LDB1 | Arina Puzriakova Gene: ldb1 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Hydrocephalus v5.4 | LDB1 |
Arina Puzriakova gene: LDB1 was added gene: LDB1 was added to Hydrocephalus. Sources: Literature Q4_25_promote_green tags were added to gene: LDB1. Mode of inheritance for gene: LDB1 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: LDB1 were set to 39680505; 38091987; 33077954 Phenotypes for gene: LDB1 were set to Congenital hydrocephalus, MONDO:0016349 Review for gene: LDB1 was set to GREEN Added comment: - 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 |
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