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TBX6 missense variants expand the mutational spectrum in a non‐Mendelian inheritance disease
Author(s) -
Chen Weisheng,
Lin Jiachen,
Wang Lianlei,
Li Xiaoxin,
Zhao Sen,
Liu Jiaqi,
Akdemir Zeynep C.,
Zhao Yanxue,
Du Renqian,
Ye Yongyu,
Song Xiaofei,
Zhang Yuanqiang,
Yan Zihui,
Yang Xinzhuang,
Lin Mao,
Shen Jianxiong,
Wang Shengru,
Gao Na,
Yang Ying,
Liu Ying,
Li Wenli,
Liu Jia,
Zhang Na,
Yang Xu,
Xu Yuan,
Zhang Jianguo,
Delgado Mauricio R.,
Posey Jennifer E.,
Qiu Guixing,
Rios Jonathan J.,
Liu Pengfei,
Wise Carol A.,
Zhang Feng,
Wu Zhihong,
Lupski James R.,
Wu Nan
Publication year - 2020
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.23907
Subject(s) - biology , genetics , missense mutation , exome sequencing , allele , mendelian inheritance , haploinsufficiency , compound heterozygosity , locus (genetics) , allelic heterogeneity , genetic counseling , gene , mutation , phenotype
Abstract Congenital scoliosis (CS) is a birth defect with variable clinical and anatomical manifestations due to spinal malformation. The genetic etiology underlying about 10% of CS cases in the Chinese population is compound inheritance by which the gene dosage is reduced below that of haploinsufficiency. In this genetic model, the trait manifests as a result of the combined effect of a rare variant and common pathogenic variant allele at a locus. From exome sequencing (ES) data of 523 patients in Asia and two patients in Texas, we identified six TBX6 gene‐disruptive variants from 11 unrelated CS patients via ES and in vitro functional testing. The in trans mild hypomorphic allele was identified in 10 of the 11 subjects; as anticipated these 10 shared a similar spinal deformity of hemivertebrae. The remaining case has a homozygous variant in TBX6 (c.418C>T) and presents a more severe spinal deformity phenotype. We found decreased transcriptional activity and abnormal cellular localization as the molecular mechanisms for TBX6 missense loss‐of‐function alleles. Expanding the mutational spectrum of TBX6 pathogenic alleles enabled an increased molecular diagnostic detection rate, provided further evidence for the gene dosage‐dependent genetic model underlying CS, and refined clinical classification.