Comprehensive genotype‐phenotype correlation in AP‐4 deficiency syndrome; Adding data from a large cohort of Iranian patients

Abstract

Mutations in adaptor protein complex-4 (AP-4) genes have first been identified in 2009, causing a phenotype termed as AP-4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype-phenotype correlation of the AP-4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease-causing variants in AP-4 complex subunits, using next-generation sequencing. Furthermore, by comparing genotype-phenotype findings of those affected individuals with previously reported patients, we further refine the genotype-phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP-4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort

“…The AP4 complex is one of the five members of the Adapter Protein family, which is involved in the post-Golgi pathways in transporting cargo from the trans-Golgi to endosomes and autophagosomal structures. 19 This complex consists of four subunits, encoded by AP4B1, AP4E1, AP4M1, and AP4S1. The AP4 complex could be involved in the transportation of various cargoes, including low-density lipoprotein receptor, amyloid precursor protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, ATG9A, and δ2 glutamate receptors.…”

“…[21][22][23][24][25][26] Mutations in AP4 complex genes cause AP4 deficiency syndrome, which is characterized by intellectual disability, spastic tetraplegia, developmental delay, speech disorder, microcephaly, and inability to walk. 19 Abnormal spindle-like, microcephaly-associated; ASPM ASPM encodes ASPM, a protein localized at the centrosome of apical neural progenitor cells that is involved in mitotic spindle orientation during embryonic neurogenesis 27 and is important for the correct proliferation and differentiation of neural progenitor cells during brain development. 28 Mutations in this gene cause autosomal recessive primary microcephaly 5, characterized by ID, microcephaly, sloping forehead, hypoplasia of the corpus callosum, simplified gyral pattern, and speech problems.…”

Putative founder effect of Arg338* AP4M1 (SPG50) variant causing severe intellectual disability, epilepsy and spastic paraplegia: Report of three families

“…The clinical phenotypes of patients with variants in any of the four AP4 subunits are very similar and can be grouped together under "AP4 deficiency syndrome." [1][2][3] This syndrome of autosomal recessive transmission manifests with intellectual disability and spastic paraplegia. 4,5 Variants in AP4M1 gene (MIM *602296) have been identified in several patients.…”

Whole-Exome Sequencing for Identifying Genetic Causes of Intellectual Developmental Disorders

“… 1 As a result of genetic variation, infection, poisoning, head injury, craniocerebral malformation or endocrine abnormalities and other harmful factors, the brain of the fetus or infant cannot develop normally or completely, so that the development of intellectual activities stays at a relatively low stage. 2 …”