@article {708, title = {Genetic and molecular mechanism for distinct clinical phenotypes conveyed by allelic truncating mutations implicated in FBN1.}, journal = {Mol Genet Genomic Med}, volume = {8}, year = {2020}, month = {2020 01}, pages = {e1023}, abstract = {

BACKGROUND: The molecular and genetic mechanisms by which different single nucleotide variant alleles in specific genes, or at the same genetic locus, cause distinct disease phenotypes often remain unclear. Allelic truncating mutations of FBN1 could cause either classical Marfan syndrome (MFS) or a more complicated phenotype associated with Marfanoid-progeroid-lipodystrophy syndrome (MPLS).

METHODS: We investigated a small cohort, encompassing two classical MFS and one MPLS subjects~from China, whose clinical presentation included scoliosis potentially requiring surgical intervention. Targeted next generation sequencing was performed on all the participants. We analyzed the molecular diagnosis, clinical features, and the potential molecular mechanism involved in the MPLS subject in our cohort.

RESULTS: We report a novel de novo FBN1 mutation for the first Chinese subject~with MPLS, a more complicated fibrillinopathy, and two subjects~with more classical MFS. We further predict that the MPLS truncating mutation, and others previously reported, is prone to escape the nonsense-mediated decay (NMD), while MFS mutations are predicted to be subjected to NMD. Also, the MPLS mutation occurs within the glucogenic hormone asprosin domain of FBN1. In vitro experiments showed that the single MPLS mutation p.Glu2759Cysfs*9 appears to perturb proper FBN1 protein aggregation as compared with the~classical MFS mutation p.Tyr2596Thrfs*86. Both mutations appear to upregulate SMAD2 phosphorylation in vitro.

CONCLUSION: We provide direct evidence that a dominant-negative interaction of FBN1 potentially explains the complex MPLS phenotypes through genetic and functional analysis. Our study expands the mutation spectrum of FBN1 and highlights the potential molecular mechanism for MPLS.

}, keywords = {Adolescent, Adult, Child, Female, Fibrillin-1, HEK293 Cells, Humans, Lipodystrophy, Marfan Syndrome, Mutation, Phenotype, Progeria, Protein Domains, Smad2 Protein}, issn = {2324-9269}, doi = {10.1002/mgg3.1023}, author = {Lin, Mao and Liu, Zhenlei and Liu, Gang and Zhao, Sen and Li, Chao and Chen, Weisheng and Coban Akdemir, Zeynep and Lin, Jiachen and Song, Xiaofei and Wang, Shengru and Xu, Qiming and Zhao, Yanxue and Wang, Lianlei and Zhang, Yuanqiang and Yan, Zihui and Liu, Sen and Liu, Jiaqi and Chen, Yixin and Zuo, Yuzhi and Yang, Xu and Sun, Tianshu and Yang, Xin-Zhuang and Niu, Yuchen and Li, Xiaoxin and You, Wesley and Qiu, Bintao and Ding, Chen and Liu, Pengfei and Zhang, Shuyang and Carvalho, Claudia M B and Posey, Jennifer E and Qiu, Guixing and Lupski, James R and Wu, Zhihong and Zhang, Jianguo and Wu, Nan} } @article {954, title = {Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome.}, journal = {Kidney Int}, volume = {98}, year = {2020}, month = {2020 10}, pages = {1020-1030}, abstract = {

Congenital anomalies of the kidney and urinary tract (CAKUTs) are the most common cause of chronic kidney disease in children. Human 16p11.2 deletions have been associated with CAKUT, but the responsible molecular mechanism remains to be illuminated. To explore this, we investigated 102 carriers of 16p11.2 deletion from multi-center cohorts, among which we retrospectively ascertained kidney morphologic and functional data from 37 individuals (12 Chinese and 25 Caucasian/Hispanic). Significantly higher CAKUT rates were observed in 16p11.2 deletion carriers (about 25\% in Chinese and 16\% in Caucasian/Hispanic) than those found in the non-clinically ascertained general populations (about 1/1000 found at autopsy). Furthermore, we identified seven additional individuals with heterozygous loss-of-function variants in TBX6, a gene that maps to the 16p11.2 region. Four of these seven cases showed obvious CAKUT. To further investigate the role of TBX6 in kidney development, we engineered mice with mutated Tbx6 alleles. The Tbx6 heterozygous null (i.e., loss-of-function) mutant (Tbx6) resulted in 13\% solitary kidneys. Remarkably, this incidence increased to 29\% in a compound heterozygous model (Tbx6) that reduced Tbx6 gene dosage to below haploinsufficiency, by combining the null allele with a novel mild hypomorphic allele (mh). Renal hypoplasia was also frequently observed in these Tbx6-mutated mouse models. Thus, our findings in patients and mice establish TBX6 as a novel gene involved in CAKUT and its gene dosage insufficiency as a potential driver for kidney defects observed in the 16p11.2 microdeletion syndrome.

}, issn = {1523-1755}, doi = {10.1016/j.kint.2020.04.045}, author = {Yang, Nan and Wu, Nan and Dong, Shuangshuang and Zhang, Ling and Zhao, Yanxue and Chen, Weisheng and Du, Renqian and Song, Chengcheng and Ren, Xiaojun and Liu, Jiaqi and Pehlivan, Davut and Liu, Zhenlei and Rao, Jia and Wang, Chunyan and Zhao, Sen and Breman, Amy M and Xue, Huadan and Sun, Hao and Shen, Jianxiong and Zhang, Shuyang and Posey, Jennifer E and Xu, Hong and Jin, Li and Zhang, Jianguo and Liu, Pengfei and Sanna-Cherchi, Simone and Qiu, Guixing and Wu, Zhihong and Lupski, James R and Zhang, Feng} } @article {682, title = {TBX6-associated congenital scoliosis (TACS) as a clinically distinguishable subtype of congenital scoliosis: further evidence supporting the compound inheritance and TBX6 gene dosage model.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 07}, pages = {1548-1558}, abstract = {

PURPOSE: To characterize clinically measurable endophenotypes, implicating the TBX6 compound inheritance model.

METHODS: Patients with congenital scoliosis (CS) from China(N = 345, cohort 1), Japan (N = 142, cohort 2), and the United States (N = 10, cohort 3) were studied. Clinically measurable endophenotypes were compared according to the TBX6 genotypes. A mouse model for Tbx6 compound inheritance (N = 52) was investigated by micro computed tomography (micro-CT). A clinical diagnostic algorithm (TACScore) was developed to assist in clinical recognition of TBX6-associated CS (TACS).

RESULTS: In cohort 1, TACS patients (N = 33) were significantly younger at onset than the remaining CS patients (P = 0.02), presented with one or more hemivertebrae/butterfly vertebrae (P = 4.9 {\texttimes} 10), and exhibited vertebral malformations involving the lower part of the spine (T8-S5, P = 4.4 {\texttimes} 10); observations were confirmed in two replication cohorts. Simple rib anomalies were prevalent in TACS patients (P = 3.1 {\texttimes} 10), while intraspinal anomalies were uncommon (P = 7.0 {\texttimes} 10). A clinically usable TACScore was developed with an area under the curve (AUC) of 0.9 (P = 1.6 {\texttimes} 10). A Tbx6 mouse model supported that a~gene dosage effect underlies the TACS phenotype.

CONCLUSION: TACS is a clinically distinguishable entity with consistent clinically measurable endophenotypes. The type and distribution of vertebral column abnormalities in TBX6/Tbx6 compound inheritance implicate subtle perturbations in gene dosage as a cause of spine developmental birth defects responsible for about 10\% of CS.

}, issn = {1530-0366}, doi = {10.1038/s41436-018-0377-x}, author = {Liu, Jiaqi and Wu, Nan and Yang, Nan and Takeda, Kazuki and Chen, Weisheng and Li, Weiyu and Du, Renqian and Liu, Sen and Zhou, Yangzhong and Zhang, Ling and Liu, Zhenlei and Zuo, Yuzhi and Zhao, Sen and Blank, Robert and Pehlivan, Davut and Dong, Shuangshuang and Zhang, Jianguo and Shen, Jianxiong and Si, Nuo and Wang, Yipeng and Liu, Gang and Li, Shugang and Zhao, Yanxue and Zhao, Hong and Chen, Yixin and Zhao, Yu and Song, Xiaofei and Hu, Jianhua and Lin, Mao and Tian, Ye and Yuan, Bo and Yu, Keyi and Niu, Yuchen and Yu, Bin and Li, Xiaoxin and Chen, Jia and Yan, Zihui and Zhu, Qiankun and Meng, Xiaolu and Chen, Xiaoli and Su, Jianzhong and Zhao, Xiuli and Wang, Xiaoyue and Ming, Yue and Li, Xiao and Raggio, Cathleen L and Zhang, Baozhong and Weng, Xisheng and Zhang, Shuyang and Zhang, Xue and Watanabe, Kota and Matsumoto, Morio and Jin, Li and Shen, Yiping and Sobreira, Nara L and Posey, Jennifer E and Giampietro, Philip F and Valle, David and Liu, Pengfei and Wu, Zhihong and Ikegawa, Shiro and Lupski, James R and Zhang, Feng and Qiu, Guixing} } @article {526, title = {The coexistence of copy number variations (CNVs) and single nucleotide polymorphisms (SNPs) at a locus can result in distorted calculations of the significance in associating SNPs to disease.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Jul}, pages = {553-567}, abstract = {

With the recent advance in genome-wide association studies (GWAS), disease-associated single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) have been extensively reported. Accordingly, the issue of incorrect identification of recombination events that can induce the distortion of multi-allelic or hemizygous variants has received more attention. However, the potential distorted calculation bias or significance of a detected association in a GWAS due to the coexistence of CNVs and SNPs in the same genomic region may remain under-recognized. Here we performed the association study within a congenital scoliosis (CS) cohort whose genetic etiology was recently elucidated as a compound inheritance model, including mostly one rare variant deletion CNV null allele and one common variant non-coding hypomorphic haplotype of the TBX6 gene. We demonstrated that the existence of a deletion in TBX6 led to an overestimation of the contribution of the SNPs on the hypomorphic allele. Furthermore, we generalized a model to explain the calculation bias, or distorted significance calculation for an association study, that can be {\textquoteright}induced{\textquoteright} by CNVs at a locus. Meanwhile, overlapping between the disease-associated SNPs from published GWAS and common CNVs (overlap 10\%) and pathogenic/likely pathogenic CNVs (overlap 99.69\%) was significantly higher than the random distribution (p < 1 {\texttimes} 10 and p = 0.034, respectively), indicating that such co-existence of CNV and SNV alleles might generally influence data interpretation and potential outcomes of a GWAS. We also verified and assessed the influence of colocalizing CNVs to the detection sensitivity of disease-associated SNP variant alleles in another adolescent idiopathic scoliosis (AIS) genome-wide association study. We proposed that detecting co-existent CNVs when evaluating the association signals between SNPs and disease traits could improve genetic model analyses and better integrate GWAS with robust Mendelian principles.

}, keywords = {Adolescent, Congenital Abnormalities, DNA Copy Number Variations, Female, Genetic Predisposition to Disease, Genome, Human, Genome-Wide Association Study, Genomics, Genotype, Haplotypes, Humans, Phenotype, Polymorphism, Single Nucleotide, Scoliosis}, issn = {1432-1203}, doi = {10.1007/s00439-018-1910-3}, author = {Liu, Jiaqi and Zhou, Yangzhong and Liu, Sen and Song, Xiaofei and Yang, Xin-Zhuang and Fan, Yanhui and Chen, Weisheng and Akdemir, Zeynep Coban and Yan, Zihui and Zuo, Yuzhi and Du, Renqian and Liu, Zhenlei and Yuan, Bo and Zhao, Sen and Liu, Gang and Chen, Yixin and Zhao, Yanxue and Lin, Mao and Zhu, Qiankun and Niu, Yuchen and Liu, Pengfei and Ikegawa, Shiro and Song, You-Qiang and Posey, Jennifer E and Qiu, Guixing and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} }