Genome-Scale Analysis Identifies Novel Genetic Vulnerabilities in Allan Herndon Dudley Syndrome

Allan Herndon Dudley syndrome (AHDS), an X-linked condition, constitutes a rare, progressive, clinically heterogeneous disorder involving severe psychomotor retardation and peripheral thyrotoxicosis, consequent to thyroid hormone transporter SLC16A2 mutations. However, direct targeted screening for SLC16A2 mutations in patients with AHDS partly predicts phenotypic heterogeneity although similar mutations are associated with differences in clinical phenotype severity, suggesting the existence of additional gene-related AHDS subtypes as in other types of mental retardation. Specifically, we report a family with AHDS comprising five individuals, including three male children (of whom two were monozygotic twins). In this pedigree, we identified a linkage of two X-linked inherited genes including SLC16A2 (p. G453R) and KIF4A (p. A491V) as a putative AHDS etiology. Additionally, we identified an independent cluster of structural variations (SVs)-enriched potential AHDS susceptibility genes, which might be as the neuronal genetic vulnerabilities likely contributing to AHDS. Our observations suggest that AHDS phenotype heterogeneity may arise from multi-genetic contributions. These familial cases, involving likely novel AHDS subtypes, provide an opportunity to explain neuropsychiatric retardation. An integrated next generation mapping and whole genome sequencing strategy for refining AHDS diagnosis and clinical categorization is recommended inclusive of cases with the related overlapping phenotypes in psychomotor disabilities. Funding Statement: This work was supported by the Stem Cell Clinical Trial Project of the National Health and Family Planning Commission of China and the China Food and Drug Administration (Registration No. CMR-201611-1003), (Medical Research Registry and Management Systemhttp://114.255.123.14), and the National Nature Science Foundation of China (Grant No. 81471308). Declaration of Interests: We declare no conflict of interest. Ethics Approval Statement: Informed consent was obtained from the parents, and the study was approved by the Research Ethics Boards at the First Affiliated Hospital of Dalian Medical University (approval number: YJ-KY-FB-2017-27)