Early onset or syndromic epilepsy

Gene: LMAN2L

Green List (high evidence)

Comment on list classification: There are now 3 unrelated probands reported in literature with biallelic LMAN2L variants and early-onset epilepsy. There is also one pedigree reported with a heterozygous LMAN2L variant segregating with tonic clonic seizures. Hence, this gene can be promoted to Green at the next update, with MOI set to 'BIALLELIC, autosomal or pseudoautosomal', until more evidence emerges for the dominant association.

Created: 13 Aug 2026, 11:35 a.m. | Last Modified: 13 Aug 2026, 11:36 a.m.

Panel Version: 9.60

Comment on phenotypes: OMIM phenotype updated 13th Aug 2026.

Created: 13 Aug 2026, 11:33 a.m. | Last Modified: 13 Aug 2026, 11:33 a.m.

Panel Version: 9.59

PMID: 40221759 Wang et al. 2025
Report of 2 sibs with LMAN2L compound heterozygous variants, c.476A>G, p.D159G and c.1060_1061del, p.S354Pfs*29. Some family history of epilepsy (parents' cousins) but no ID history. Parents are not related.
Proband (Case 1, female) had intellectual disability, severe developmental delays, and epileptic seizures at the age of 2 months. The child has a low immunity and is hospitalized for severe pneumonia about 4–5 times a year. She also had developmental dysplasia of the hip and low muscle tone.
Case 2 - male, hospitalised for feeding difficulties; bilateral hearing impariment noted; he had edema, low muscle tone, and an umbilical hernia. Developed tonic clonic seizures at 2 months.
Epilepsy was resistant to medication in both sibs.

PMID: 37667433 Zhou et al., 2023
Report of a Chinese female proband, 3yo, from a non-consanguineous family with comp het LMAN2L variants: c.902del (p.F301Sfs∗8) and c.256C>T (p.R86C). Method: Trio WES. Patient was diagnosed with general growth retardation, epilepsy (tonic seizures with onset at 2 months), and hearing loss. She showed a general developmental delay. She had difficulty in sitting, standing, walking, speaking, and making social interactions. Hypotonia was also noted. Parents, het carriers for a variant each, were unaffected.

Created: 13 Aug 2026, 11:30 a.m. | Last Modified: 13 Aug 2026, 11:30 a.m.

Panel Version: 9.57

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Intellectual developmental disorder, autosomal dominant 69, OMIM:617863; ?Intellectual developmental disorder, autosomal recessive 52, OMIM:61688; intellectual disability, autosomal recessive 52, MONDO:0014815; intellectual developmental disorder, autosomal dominant 69, MONDO:0029465

Publications

• 37667433
• 40221759

I don't know

PMID: 26566883 (2015) - One consanguineous family with 7 individuals with ID and epilepsy. Five individuals presented mild epileptic seizures in the first year of life, until the age of 5 years when seizures stopped spontaneously without any medication. Typical seizure episodes lasted for 3 to 5 min. Epilepsy was also reported in two other family members, who died at the age of 7 and 16 years and therefore could not be included in the study. A homozygous LMAN2L missense variant (c.158 G>A, p.R53Q) segregated with disease in family, and unaffected family members were heterozygous variant carriers. No functional studies.

PMID: 31020005 (2019) - One non-consanguineous family with 4 affected, harbouring a heterozygous frameshift LMAN2L variant (c.1073delT, p.Phe358Serfs*16) which segregated with disease in the family. All suffered generalised tonic‐clonic seizures in childhood, however all had undergone remission with normalized EEG by adolescence. Functional studies show the variant eliminates LMAN2L's endoplasmic reticulum retention signal and mislocalizes the protein from that compartment to the plasma membrane.
Sources: Literature

Created: 31 Jul 2020, 12:24 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Intellectual disability; Epilepsy

Publications

• 31020005
• 26566883