Background: The number of reported genes causing non-syndromic autosomal recessive intellectual disability (NS-ARID) is increasing. For example, mutations in the ST3GAL3 gene have been reported to be associated with NS-ARID. In the present study, we aimed to determine the genetic cause of the NS-ARID in a five-generation consanguineous Iranian family. Methods: We subjected four patients with an initial diagnosis of NS-ID in an Iranian family. To identify the possible genetic cause(s), whole-exome sequencing was performed on the proband and Sanger sequencing was applied to investigate cosegregation analysis. Using in silico predictive tools, the possible impacts of the variant on the structure and function of ST3Gal-III were predicted. Results: The common clinical features were detected in all affected members who were suffering from a severe ID. Using whole-exome sequencing, a novel variant, c.704C>T or p.(Thr235Met), in exon 9 of the ST3GAL3 gene (NM_001270461.2, OMIM# 606494) was identified and verified by Sanger sequencing. This variant is located next to the VS motif of ST3Gal-III, which is a vital part of the catalytical domains. Conclusions: In the present study, we identified a novel missense variant, c.704C>T or p.(Thr235Met), in the ST3GAL3. To our knowledge, is the third variant in this gene to be associated with NS-ARID. Our findings highlight the need for further investigations into the mechanisms by which variants in ST3GAL3 contribute to neurological dysfunction.

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ATP8A2 is a P4-ATPase that flips phosphatidylserine across membranes to generate and maintain transmembrane phospholipid asymmetry. Loss-of-function variants cause severe neurodegenerative and developmental disorders. We have identified three ATP8A2 variants in unrelated Iranian families that cause intellectual disability, dystonia, below-average head circumference, mild optic atrophy, and developmental delay. Additionally, all the affected individuals displayed tooth abnormalities associated with defects in teeth development. Two variants (p.As-p825His and p.Met438Val) reside in critical functional domains of ATP8A2. These variants express at very low levels and lack ATPase activity. Inhibitor studies indicate that these variants are misfolded and degraded by the cellular proteasome. We conclude that Asp825, which coordinates with the Mg 2+ ion within the ATP binding site, and Met438 are essential for the proper folding of ATP8A2 into a functional flippase. We also provide evidence on the association of tooth abnormalities with defects in ATP8A2, thereby expanding the clinical spectrum of the associated disease.

The human dopamine transporter (hDAT) participates in dopamine homeostasis by clearing dopamine from the extracellular space using secondary active transport. Dysregulation of hDAT has been reported to be associated with different neuropsychiatric disorders. Dopamine transporter deficiency syndrome (DTDS) is a complex disease caused by defects in dopamine uptake within the synaptic cleft and patients manifest parkinsonian features. The extracellular loops are crucial for DAT activity and defects in these regions disturb dopamine transport. In the present study, a 3.5‐year‐old female in a consanguineous Iranian family with an initial diagnosis of gait imbalance and speech delay has been identified. We utilized whole‐exome sequencing (WES) to identify the possible genetic defect(s). WES identified a novel homozygous in‐frame indel variant, c.1139_1150del; p.(Gly380_Lys384delinsGlu), in the SLC6A3 gene (NM_001044.4), as the most likely disease‐susceptibility variant. This variant is located in extracellular loop 4 (EL4) of the DAT protein. Our study highlights the role of extracellular loops and shows the EL4 of hDAT as a critical region for the protein activity. The identified variant in the EL4 region of DAT is predicted to compromise DAT function and may lead to DTDS in this case. However, complementary studies are required to confirm.

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