Novel Variants in the SLC16A2 Gene Associated With Allan–Herndon–Dudley Syndrome in China

Objective This study is aimed at investigating the genetic defects and clinical features of Chinese children with SLC16A2 variants and at exploring the effects of mutant MCT8 on protein expression and subcellular localization through in vitro experiments. Methods Children with intellectual disability and abnormal serum thyroid hormone levels were screened using whole‐exome sequencing (WES). We collected patients′ clinical data and assessed their cognitive, linguistic, and motor abilities. Candidate variants were verified by Sanger sequencing, and their pathogenicity and evolutionary conservation were analyzed using in silico prediction tools. Protein expression and subcellular localization of mutant MCT8 were evaluated by Western blotting and immunofluorescence microscopy. Results Exome sequencing identified seven previously uncharacterized SLC16A2 variants in 10 unrelated male patients (nine families). These included three missense mutations (p.Ala150Thr,p.Gly208Arg, and p.Gly208Asp), three frameshift mutations (p.Leu168fs, p.Ser243Cysfs, and p.Val485fs), one deletion–insertion mutation (p.Ile328_Ala329delinsThr), and one balanced translocation, t(X,12) (q13.2; q13.13). All patients exhibited global developmental delay, axial hypotonia, dystonia, and abnormal thyroid hormone profiles. In vitro experiments demonstrated significantly reduced expression of mutant proteins compared with the wild‐type. Immunofluorescence showed that, in addition to residual plasma membrane localization, mutant proteins were also partially retained in the cytoplasm, whereas the wild‐type protein localized exclusively to the plasma membrane. Conclusion Our findings expand the genotypic and phenotypic spectrum of MCT8 deficiency. The results suggest that SLC16A2 variants lead to a loss of function through decreased protein expression and defective plasma membrane trafficking.