Malformations of cortical development

Gene: BAIAP2

Red List (low evidence)

Comment on list classification: There are 7 unrelated individuals reported in literature with de novo heterozygous missense variants in BAIAP2. 6 individuals presented with developmental and epileptic encephalopathy (PMID: 41133935), while 1 individual was diagnosed with classic lissencephaly (PMID: 38149472). Baiap2 knockdown in mouse causes abnormalities in neuronal migration, morphogenesis, and differentiation (PMID: 38149472). As only 1 patient presented with lissencephaly, BAIAP2 should be rated Red for Malformations of cortical development, until more evidence emerges.

Created: 17 Nov 2025, 1:51 p.m. | Last Modified: 17 Nov 2025, 1:51 p.m.

Panel Version: 7.17

PMID: 38149472 Tsai et al., 2024
6yo individual from Taiwan with a de novo c.85C>T, p.Arg29Trp variant in BAIAP2 with lissencephaly. Method: WES +Sanger.
Phenotype: severe global developmental delay since infancy, lack of speech development, poor motor milestone achievement; refractory epilepsy with multiple seizure patterns, including focal, myoclonic, tonic, absence and tonic-clonic seizures, and epileptic spasms since infancy. Classical lissencephaly features noted on brain MRI at 5yrs.
Functional evidence: Baiap2 knockdown in mouse cause abnormalities in neuronal migration, morphogenesis, and differentiation. Expression of p.Arg29Trp failed to rescue the defect - suggests LoF effect for this variant.

PMID: 41133935 Zhang et al., 2025
6 patients reported with de novo missense variants in BAIAP2. All six patients exhibited severe infantile or early childhood onset epilepsy - refractory seizures in four individuals. Age of onset of epilepsy: 5 mo - 1 yr 7 mo. Additionally, 6/6 individuals presented with global developmental delay; 4/6 are nonverbal and 2/6 only know a few words; ID severity was variable: mild (1/6), moderate-severe (3/6), and severe-profound (2/6). Diverse ancestry: Chinese, British, Turkish, White Kosovar, Austrian. Patients were heterozygous for the following missense variants: c.1088G>A, p.Arg363His; c.1019C>A, p.Thr340Lys; c.1018A>G, p.Thr340Ala; c.566A>T, p.Glu189Val; c.1019C>T, p.Thr340Ile; c.1024C>G, p.Pro342Ala. The variants are not present in gnomAD v4.1.0.
Authors pose that 5/6 variants reported are likely to destabilise binding of 14-3-3 to BAIAP2.

Functional evidence: PMID: 30696821 Kast & Dominguez, 2019
Protein 14-3-3 binds to two pairs of sites in the linker between the CRIB-PR and SH3 domains of BAIAP2 (pT340/pT360 or pT340/pS366) - consistent with the hotspot region seen in patients (5/6 variants reported in PMID: 41133935 are in the 340-366 region). The binding of 14-3-3 is crucial for inhibition of BAIAP2 action - particularly regulating actin and filopodia formation.

This gene is not yet associated with a phenotype in OMIM (accessed 17th Nov 2025).
Sources: Other

Created: 17 Nov 2025, 1:50 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
developmental and epileptic encephalopathy, MONDO:0100620; classic lissencephaly, MONDO:0015146

Publications

• 30696821
• 38149472
• 41133935