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16 Aug 2026	Intellectual disability v11.17	LDB1	Achchuthan Shanmugasundram changed review comment from: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder. N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen.; to: PMID:42320471 (2026) reported a cohort of 16 individuals with de novo LDB1 variants, of which 14 patients presented with developmental delay, 13 patients with speech delay and 8 patients with motor delay. There were eight other patients reported previously. Developmental delay was present in 9/11 individuals with N-terminal LGD/DD missense variants and 7/7 individuals with C-terminal LID-affecting variants, speech delay present in 10/10 and 5/5, and motor delay present in 5/9 and 5/5 respectively. Unlike the ventriculomegaly phenotype, developmental delay occurs across both N-terminal and C-terminal variant classes, indicating it is a core, mechanism-independent feature of LDB1-related neurodevelopmental disorder. N-terminal DD missense variants impair LDB1 homodimerization through loss-of-function, while C-terminal LID variants abolish LHX2 binding via a dominant-negative mechanism, both disrupting transcriptional complexes required for neurogenesis. In Drosophila, neuronal knockdown of the LDB1 ortholog chi impaired motor behavior, and both variant types failed to properly rescue this phenotype, confirming LDB1 dysfunction causally contributes to neurological/developmental impairment. This gene has not yet been associated with relevant phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 16 August 2026).
16 Oct 2023	Intellectual disability v5.313	LHX2	Eleanor Williams Tag gene-checked tag was added to gene: LHX2.
16 Oct 2023	Intellectual disability v5.313	LHX2	Eleanor Williams commented on gene: LHX2
11 Oct 2023	Intellectual disability v5.296	LHX2	Arina Puzriakova Phenotypes for gene: LHX2 were changed from neurodevelopmental disorder to neurodevelopmental disorder, MONDO:0700092
11 Oct 2023	Intellectual disability v5.295	LHX2	Arina Puzriakova Tag Q2_23_promote_green was removed from gene: LHX2.
11 Oct 2023	Intellectual disability v5.286	LHX2	Arina Puzriakova reviewed gene: LHX2: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown
11 Oct 2023	Intellectual disability v5.286	LHX2	Arina Puzriakova Source NHS GMS was added to LHX2. Source Expert Review Green was added to LHX2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
09 May 2023	Intellectual disability v5.109	LHX2	Sarah Leigh Classified gene: LHX2 as Amber List (moderate evidence)
09 May 2023	Intellectual disability v5.109	LHX2	Sarah Leigh Added comment: Comment on list classification: There is enough evidence for this gene to be rated GREEN at the next major review.
09 May 2023	Intellectual disability v5.109	LHX2	Sarah Leigh Gene: lhx2 has been classified as Amber List (Moderate Evidence).
09 May 2023	Intellectual disability v5.108	LHX2	Sarah Leigh gene: LHX2 was added gene: LHX2 was added to Intellectual disability - microarray and sequencing. Sources: Literature Q2_23_promote_green tags were added to gene: LHX2. Mode of inheritance for gene: LHX2 was set to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown Publications for gene: LHX2 were set to 37057675 Phenotypes for gene: LHX2 were set to neurodevelopmental disorder Review for gene: LHX2 was set to GREEN Added comment: Not associated with a phenotype in OMIM, Gen2Phen or MONDO. PMID: 37057675 reports 17 predominanly de novo LHX2 variants in a panel of patients with a variable neurodevelopmental disorder. Haploinsufficiency and functional studies are supportive of a loss-of-function pathogenic action of the reported LHX2 variants. Sources: Literature