A biallelic loss-of-function variant in TMEM147 causes profound intellectual disability and spasticity

Area of Science:

• Neurogenetics
• Developmental Biology
• Molecular Medicine

Background:

• Intellectual disability (ID) is a common neurodevelopmental disorder with high genetic heterogeneity.
• Biallelic variants in TMEM147 have been associated with ID and dysmorphic features.
• TMEM147 plays a role in endoplasmic reticulum and nuclear envelope functions, including membrane protein biogenesis.

Purpose of the Study:

• To investigate the genetic cause of intellectual disability in a consanguineous family.
• To identify novel variants in TMEM147 and characterize their associated phenotype.

Main Methods:

• Whole exome sequencing was performed to identify potential causative variants.
• A novel loss-of-function variant (NM_001242597.2:c.193-197del) in TMEM147 was identified.
• Sanger sequencing was used to validate the identified variant.

Main Results:

• Two patients from a consanguineous family presented with intellectual disability and spasticity.
• A novel loss-of-function variant in TMEM147 was identified as the likely cause.
• The findings align with previous reports of TMEM147-related ID, with spasticity representing a phenotypic expansion.

Conclusions:

• This study provides further evidence for the pathogenicity of TMEM147 mutations in intellectual disability.
• The identified variant expands the known phenotypic spectrum associated with TMEM147, including spasticity.
• TMEM147 is confirmed as a significant gene in neurodevelopmental disorders.