Genetic Epilepsy

Gene: TRAPPC2L

Red List (low evidence)

PMID: 36849228
Described the first pathogenic protein-truncating variant in the TRAPPC2L gene found at a homozygous state in two affected siblings. This report provides key genetic evidence invaluable to establishing the gene-disease relationship for this gene and important insights into the TRAPPC2L phenotype. Regression, seizures and postnatal microcephaly initially described are NOT constant features. Acute episodes of infection do not contribute to the neurological course. HyperCKaemia is part of the clinical picture.

Rating remains red in this panel as seizures not reported in all families including the above two sibs.

Created: 14 Dec 2023, 5:57 a.m. | Last Modified: 14 Dec 2023, 5:57 a.m.

Panel Version: 0.2028

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, MIM#618331

Publications

• 36849228
• 30120216
• 32843486

Red List (low evidence)

Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Red on this panel as seizures not reported in all families. PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect. The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11. PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family. Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.
Sources: Literature

Created: 2 Sep 2020, 11:59 p.m. | Last Modified: 3 Sep 2020, midnight

Panel Version: 0.831

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331

Publications

• 30120216
• 32843486

I don't know

Total of three families, but two share a founder variant, and there are some disparities between the clinical presentations reported in the two publications. Rating Amber as additional cases required to delineate the genotype-phenotype relationship.

PMID: 30120216 (2018) - Two unrelated probands with an identical homozygous missense (c.109G>T, p.Asp37Tyr) variant in TRAPPC2L. Both individuals presented neurodevelopmental delay, febrile illness-induced encephalopathy, and episodic rhabdomyolysis, followed by developmental arrest, seizures and tetraplegia. The variant segregated with the phenotype in each family, and haplotype analysis suggested a founder effect.

The mutant protein was expressed in patient fibroblasts, but displayed membrane trafficking delays. Studies in yeast showed that the variant impaired interaction with TRAPPC10, and increased levels of the active RAB11.


PMID: 32843486 (2020) - In an Ashkenazi Jewish family with three affected sibs with GDD/ID, WGS revealed a segregating homozygous missense variant (c.5G>C, p.Ala2Gly) in the TRAPPC2L gene. No seizures, brain MRI abnormalities, or illness provoked regression were documented in this family.

Comparable to the previous study, the variant resulted in delayed ER-to-Golgi trafficking and elevated levels of active RAB11. Studies using yeast and in vitro binding, showed that the variant disrupted interaction with another core TRAPP protein, TRAPPC6a.

Sources: Literature

Created: 2 Sep 2020, 4:07 p.m. | Last Modified: 2 Sep 2020, 4:10 p.m.

Panel Version: 0.4134

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Encephalopathy, progressive, early-onset, with episodic rhabdomyolysis, 618331

Publications

• 30120216
• 32843486