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

44 Pages Posted: 4 Oct 2018

See all articles by Liang Wang

Liang Wang

Dalian University - Dalian Medical University

Chengqi Xin

Dalian University - Dalian Medical University

Xiaoyan Li

Dalian University - Dalian Medical University

Yang Jiao

Dalian University - Dalian Medical University

Runjie Li

Dalian Municipal Women and Children’s Medical Center

Fan Song

Dalian University - Dalian Medical University

Wanming Cui

Dalian University - Dalian Medical University

Ying Wang

Dalian University - Dalian Medical University

Ying Li

Dalian University - Dalian Medical University

Jing Liu

Dalian University - Stem Cell Clinical Research Center

More...

Abstract

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)

Keywords: Allan Herndon Dudley syndrome (AHDS), Structural Variations, KIF4A, Genetic Susceptibility

Suggested Citation

Wang, Liang and Xin, Chengqi and Li, Xiaoyan and Jiao, Yang and Li, Runjie and Song, Fan and Cui, Wanming and Wang, Ying and Li, Ying and Liu, Jing, Genome-Scale Analysis Identifies Novel Genetic Vulnerabilities in Allan Herndon Dudley Syndrome (September 18, 2018). Available at SSRN: https://ssrn.com/abstract=3251496 or http://dx.doi.org/10.2139/ssrn.3251496

Liang Wang

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Chengqi Xin

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Xiaoyan Li

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Yang Jiao

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Runjie Li

Dalian Municipal Women and Children’s Medical Center ( email )

No.3 of Guihuayihao Road
Dalian, 116000
China

Fan Song

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Wanming Cui

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Ying Wang

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Ying Li

Dalian University - Dalian Medical University ( email )

Fuguo street 81# 3-4-2
Dalian, Liao Ning 116023
China

Jing Liu (Contact Author)

Dalian University - Stem Cell Clinical Research Center ( email )

No. 193, Lianhe Road
Dalian, 116011
China