Dataset Information

TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.

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.

SUBMITTER: Chen W

PROVIDER: S-EPMC7061259 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.

Chen Weisheng W Lin Jiachen J Wang Lianlei L Li Xiaoxin X Zhao Sen S Liu Jiaqi J Akdemir Zeynep C ZC Zhao Yanxue Y Du Renqian R Ye Yongyu Y Song Xiaofei X Zhang Yuanqiang Y Yan Zihui Z Yang Xinzhuang X Lin Mao M Shen Jianxiong J Wang Shengru S Gao Na N Yang Ying Y Liu Ying Y Li Wenli W Liu Jia J Zhang Na N Yang Xu X Xu Yuan Y Zhang Jianguo J Delgado Mauricio R MR Posey Jennifer E JE Qiu Guixing G Rios Jonathan J JJ Liu Pengfei P Wise Carol A CA Zhang Feng F Wu Zhihong Z Lupski James R JR Wu Nan N

Human mutation 20190926 1

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 ...[more]

PMID: 31471994

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Project description:Parkinson's disease is a common, progressive neurodegenerative disorder, affecting 3% of those older than 75 years of age. Clinically, Parkinson's disease (PD) is associated with resting tremor, postural instability, rigidity, bradykinesia, and a good response to levodopa therapy. Over the last 15 years, numerous studies have confirmed that genetic factors contribute to the complex pathogenesis of PD. Highly penetrant mutations producing rare, monogenic forms of the disease have been discovered in singular genes such as SNCA, Parkin, DJ-1, PINK 1, LRRK2, and VPS35. Unique variants with incomplete penetrance in LRRK2 and GBA have been shown to be strong risk factors for PD in certain populations. Additionally, over 20 common variants with small effect sizes are now recognized to modulate the risk for PD. Investigating Mendelian forms of PD has provided precious insight into the pathophysiology that underlies the more common idiopathic form of disease; however, no treatment methodologies have developed. Furthermore, for identified common risk alleles, the functional basis underlying risk principally remains unknown. The challenge over the next decade will be to strengthen the findings delivered through genetic discovery by assessing the direct, biological consequences of risk variants in tandem with additional high-content, integrated datasets. This review discusses monogenic risk factors and mechanisms of Mendelian inheritance of Parkinson disease. Highly penetrant mutations in SNCA, Parkin, DJ-1, PINK 1, LRRK2 and VPS35 produce rare, monogenic forms of the disease, while unique variants within LRRK2 and GBA show incomplete penetrance and are strong risk factors for PD. Additionally, over 20 common variants with small effect sizes modulate disease risk. The challenge over the next decade is to strengthen genetic findings by assessing direct, biological consequences of risk variants in tandem with high-content, integrated datasets. This article is part of a special issue on Parkinson disease.

Dataset Information

TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.

Publications

TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.

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