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Phenotypic and protein localization heterogeneity associated with AHDC1 pathogenic protein‐truncating alleles in Xia–Gibbs syndrome
Author(s) -
Khayat Michael M.,
Li He,
Chander Varuna,
Hu Jianhong,
Hansen Adam W.,
Li Shoudong,
Traynelis Josh,
Shen Hua,
Weissenberger George,
Stossi Fabio,
Johnson Hannah L.,
Lupski James R.,
Posey Jennifer E.,
Sabo Aniko,
Meng Qingchang,
Murdock David R.,
Wangler Michael,
Gibbs Richard A.
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24190
Subject(s) - biology , hypotonia , frameshift mutation , phenotype , genetics , allelic heterogeneity , genetic heterogeneity , allele , gene
Abstract Xia–Gibbs syndrome (XGS) is a rare Mendelian disease typically caused by de novo stop‐gain or frameshift mutations in the AT‐hook DNA binding motif containing 1 ( AHDC1 ) gene. Patients usually present in early infancy with hypotonia and developmental delay and later exhibit intellectual disability (ID). The overall presentation is variable, however, and the emerging clinical picture is still evolving. A detailed phenotypic analysis of 34 XGS individuals revealed five core phenotypes (delayed motor milestones, speech delay, low muscle tone, ID, and hypotonia) in more than 80% of individuals and an additional 12 features that occurred more variably. Seizures and scoliosis were more frequently associated with truncations that arise before the midpoint of the protein although the occurrence of most features could not be predicted by the mutation position. Transient expression of wild type and different patient truncated AHDC1 protein forms in human cell lines revealed abnormal patterns of nuclear localization including a diffuse distribution of a short truncated form and nucleolar aggregation in mid‐protein truncated forms. Overall, both the occurrence of variable phenotypes and the different distribution of the expressed protein reflect the heterogeneity of this syndrome.