Professionals

TRAPPC6B-related syndrome (also known as Neurodevelopmental Disorder with Microcephaly, Epilepsy, and Brain Atrophy (NEDMEBA), OMIM #617862)) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic pathogenic variants in the TRAPPC6B gene (OMIM *610397), located on chromosome 14q21.

Prevalence
The exact prevalence of TRAPPC6B-related syndrome is unknown. To date, fewer than 50 patients have been reported in the medical literature across multiple ethnic backgrounds, including Egyptian, Lebanese, Pakistani, Iranian, and other consanguineous families worldwide. The disorder is considered rare, and is likely underdiagnosed due to limited molecular testing access in populations where consanguinity is common.

Inheritance
TRAPPC6B-related syndrome follows an autosomal recessive inheritance pattern. Both parents of an affected individual are typically heterozygous carriers and are clinically unaffected. Consanguinity has been reported in the majority of published families.

Clinical characteristics
All affected individuals present with microcephaly, global developmental delay/intellectual disability, and early-onset seizures. Autistic features, hypotonia, and progressive neurological deterioration have also been reported in a subset of patients.

Molecular characteristics
Pathogenic variants in TRAPPC6Bdisrupt the function of the TRAPP II (Transport Protein Particle) complex, which is essential for vesicle trafficking between the endoplasmic reticulum (ER) and the Golgi apparatus. The majority of reported pathogenic variants are homozygous loss-of-function mutations (splice-site and nonsense variants).

Genetic Counselling
As an autosomal recessive disorder, the recurrence risk for siblings of an affected proband with carrier parents is 25%. Prenatal and preimplantation genetic diagnosis are available when the familial variant has been identified.