# A Novel AP4M1 Variant in an Iranian Child with Spastic Paraplegia 50: A Case Report and Molecular Docking Approach

## TL;DR

A rare genetic disorder called SPG50 was identified in an Iranian child through a novel AP4M1 gene variant, using sequencing and molecular modeling.

## Contribution

A novel homozygous frameshift variant in AP4M1 is reported, expanding the genetic understanding of SPG50.

## Key findings

- A novel AP4M1 variant c.258delG:p.A87Pfs*44 was identified in a child with SPG50.
- Molecular modeling showed the variant disrupts intramolecular interactions in the AP4M1 protein.
- The study highlights the importance of this variant for genetic diagnosis in affected families.

## Abstract

Spastic paraplegia 50 (SPG50) is a rare autosomal recessive disorder caused by mutations in the AP4M1 gene (OMIM 602296).
It is characterized by spasticity, severe intellectual disability, and delayed or absent speech. The present study reported a case from consanguineous parents, where the affected child presented with intellectual disability, seizures, muscle weakness, and deep white matter hyperintensity. Whole exome sequencing (WES) of the proband identified a novel,
homozygous frameshift variant, c.258delG:p.A87Pfs*44, in the AP4M1 gene, which was confirmed by Sanger sequencing. This variant is predicted to cause a large truncation of the protein, leading to a loss of function. Molecular modeling and docking analyses further revealed that the loss of a substantial protein segment disrupts proper intramolecular interactions. A review of the literature on Iranian families with SPG50 yielded few reports, consistent with the disease’s rarity. This study expanded the knowledge of the clinical and genetic features of SPG50 and underscored the importance of this variant for genetic diagnosis and counseling in affected families.