@article {789, title = {Diagnostic yield and clinical impact of exome sequencing in early-onset scoliosis (EOS).}, journal = {J Med Genet}, volume = {58}, year = {2021}, month = {2021 Jan}, pages = {41-47}, abstract = {

BACKGROUND: Early-onset scoliosis (EOS), defined by an onset age of scoliosis less than 10 years, conveys significant health risk to affected children. Identification of the molecular aetiology underlying patients with EOS could provide valuable information for both clinical management and prenatal screening.

METHODS: In this study, we consecutively recruited a cohort of 447 Chinese patients with operative EOS. We performed exome sequencing (ES) screening on these individuals and their available family members (totaling 670 subjects). Another cohort of 13 patients with idiopathic early-onset scoliosis (IEOS) from the USA who underwent ES was also recruited.

RESULTS: After ES data processing and variant interpretation, we detected molecular diagnostic variants in 92 out of 447 (20.6\%) Chinese patients with EOS, including 8 patients with molecular confirmation of their clinical diagnosis and 84 patients with molecular diagnoses of previously unrecognised diseases underlying scoliosis. One out of 13 patients with IEOS from the US cohort was molecularly diagnosed. The age at presentation, the number of organ systems involved and the Cobb angle were the three top features predictive of a molecular diagnosis.

CONCLUSION: ES enabled the molecular diagnosis/classification of patients with EOS. Specific clinical features/feature pairs are able to indicate the likelihood of gaining a molecular diagnosis through ES.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106823}, author = {Zhao, Sen and Zhang, Yuanqiang and Chen, Weisheng and Li, Weiyu and Wang, Shengru and Wang, Lianlei and Zhao, Yanxue and Lin, Mao and Ye, Yongyu and Lin, Jiachen and Zheng, Yu and Liu, Jiaqi and Zhao, Hengqiang and Yan, Zihui and Yang, Yongxin and Huang, Yingzhao and Lin, Guanfeng and Chen, Zefu and Zhang, Zhen and Liu, Sen and Jin, Lichao and Wang, Zhaoyang and Chen, Jingdan and Niu, Yuchen and Li, Xiaoxin and Wu, Yong and Wang, Yipeng and Du, Renqian and Gao, Na and Zhao, Hong and Yang, Ying and Liu, Ying and Tian, Ye and Li, Wenli and Zhao, Yu and Liu, Jia and Yu, Bin and Zhang, Na and Yu, Keyi and Yang, Xu and Li, Shugang and Xu, Yuan and Hu, Jianhua and Liu, Zhe and Shen, Jianxiong and Zhang, Shuyang and Su, Jianzhong and Khanshour, Anas M and Kidane, Yared H and Ramo, Brandon and Rios, Jonathan J and Liu, Pengfei and Sutton, V Reid and Posey, Jennifer E and Wu, Zhihong and Qiu, Guixing and Wise, Carol A and Zhang, Feng and Lupski, James R 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 {774, title = {TBX6 missense variants expand the mutational spectrum in a non-Mendelian inheritance disease.}, journal = {Hum Mutat}, volume = {41}, year = {2020}, month = {2020 01}, pages = {182-195}, 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.

}, keywords = {Alleles, Cell Line, Female, Gene Expression, Genes, Reporter, Genetic Association Studies, Genetic Predisposition to Disease, Genotype, Haplotypes, Humans, Inheritance Patterns, Male, Models, Molecular, Molecular Diagnostic Techniques, Mutation, Missense, Phenotype, Protein Conformation, Radiography, Sequence Analysis, DNA, Spine, Structure-Activity Relationship, T-Box Domain Proteins, Whole Exome Sequencing}, issn = {1098-1004}, doi = {10.1002/humu.23907}, author = {Chen, Weisheng and Lin, Jiachen and Wang, Lianlei and Li, Xiaoxin and Zhao, Sen and Liu, Jiaqi and Akdemir, Zeynep C and Zhao, Yanxue and Du, Renqian and Ye, Yongyu and Song, Xiaofei and Zhang, Yuanqiang and Yan, Zihui and Yang, Xinzhuang and Lin, Mao and Shen, Jianxiong and Wang, Shengru and Gao, Na and Yang, Ying and Liu, Ying and Li, Wenli and Liu, Jia and Zhang, Na and Yang, Xu and Xu, Yuan and Zhang, Jianguo and Delgado, Mauricio R and Posey, Jennifer E and Qiu, Guixing and Rios, Jonathan J and Liu, Pengfei and Wise, Carol A and Zhang, Feng and Wu, Zhihong and Lupski, James R and Wu, Nan} } @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 {466, title = {A biallelic ANTXR1 variant expands the anthrax toxin receptor associated phenotype to tooth agenesis.}, journal = {Am J Med Genet A}, volume = {176}, year = {2018}, month = {2018 04}, pages = {1015-1022}, abstract = {

Tooth development is regulated by multiple genetic pathways, which ultimately drive the complex interactions between the oral epithelium and mesenchyme. Disruptions at any time point during this process may lead to failure of tooth development, also known as tooth agenesis (TA). TA is a common craniofacial abnormality in humans and represents the failure to develop one or more permanent teeth. Many genes and potentially subtle variants in these genes contribute to the TA phenotype. We report the clinical and genetic impact of a rare homozygous ANTXR1 variant (c.1312C>T), identified by whole exome sequencing (WES), in a consanguineous Turkish family with TA. Mutations in ANTXR1 have been associated with GAPO (growth retardation, alopecia, pseudoanodontia, and optic atrophy) syndrome and infantile hemangioma, however no clinical characteristics associated with these conditions were observed in our study family. We detected the expression of Antxr1 in oral and dental tissues of developing mouse embryos, further supporting a role for this gene in tooth development. Our findings implicate ANTXR1 as a candidate gene for isolated TA, suggest the involvement of specific hypomorphic alleles, and expand the previously known ANTXR1-associated phenotypes.

}, keywords = {Alleles, Amino Acid Substitution, Animals, Anodontia, Child, Consanguinity, Facies, Genetic Association Studies, Genotype, Humans, Male, Mice, Mutation, Neoplasm Proteins, Pedigree, Phenotype, Radiography, Receptors, Cell Surface, Whole Exome Sequencing}, issn = {1552-4833}, doi = {10.1002/ajmg.a.38625}, author = {Dinckan, Nuriye and Du, Renqian and Akdemir, Zeynep C and Bayram, Yavuz and Jhangiani, Shalini N and Doddapaneni, Harsha and Hu, Jianhong and Muzny, Donna M and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Boerwinkle, Eric and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Uyguner, Zehra O and Letra, Ariadne} } @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} } @article {523, title = {Identification of likely pathogenic and known variants in TSPEAR, LAMB3, BCOR, and WNT10A in four Turkish families with tooth agenesis.}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {689-703}, abstract = {

Tooth agenesis (TA), the failure of development of one or more permanent teeth, is a common craniofacial abnormality observed in different world populations. The genetic etiology of TA is heterogeneous; more than a dozen genes have been associated with isolated or nonsyndromic TA, and more than 80 genes with syndromic forms. In this study, we applied whole exome sequencing (WES) to identify candidate genes contributing to TA in four Turkish families. Likely pathogenic variants with a low allele frequency in the general population were identified in four disease-associated genes, including two distinct variants in TSPEAR, associated with syndromic and isolated TA in one family each; a variant in LAMB3 associated with syndromic TA in one family; and a variant in BCOR plus a disease-associated WNT10A variant in one family with syndromic TA. With the notable exception of WNT10A (Tooth agenesis, selective, 4, MIM $\#$150400), the genotype-phenotype relationships described in the present cohort represent an expansion of the clinical spectrum associated with these genes: TSPEAR (Deafness, autosomal recessive 98, MIM $\#$614861), LAMB3 (Amelogenesis imperfecta, type IA, MIM $\#$104530; Epidermolysis bullosa, junctional, MIMs $\#$226700 and $\#$226650), and BCOR (Microphthalmia, syndromic 2, MIM $\#$300166). We provide evidence supporting the candidacy of these genes with TA, and propose TSPEAR as a novel nonsyndromic TA gene. Our data also suggest potential multilocus genomic variation, or mutational burden, in a single family, involving the BCOR and WNT10A loci, underscoring the complexity of the genotype-phenotype relationship in the common complex trait of TA.

}, keywords = {Anodontia, Cell Adhesion Molecules, Child, Child, Preschool, Female, Genetic Markers, Humans, Male, Mutation, Pedigree, Phenotype, Proteins, Proto-Oncogene Proteins, Repressor Proteins, Turkey, Wnt Proteins}, issn = {1432-1203}, doi = {10.1007/s00439-018-1907-y}, author = {Du, Renqian and Dinckan, Nuriye and Song, Xiaofei and Coban-Akdemir, Zeynep and Jhangiani, Shalini N and Guven, Yeliz and Aktoren, Oya and Kayserili, H{\"u}lya and Petty, Lauren E and Muzny, Donna M and Below, Jennifer E and Boerwinkle, Eric and Wu, Nan and Gibbs, Richard A and Posey, Jennifer E and Lupski, James R and Letra, Ariadne and Uyguner, Z Oya} } @article {517, title = {Perturbations of BMP/TGF-β and VEGF/VEGFR signalling pathways in non-syndromic sporadic brain arteriovenous malformations (BAVM).}, journal = {J Med Genet}, volume = {55}, year = {2018}, month = {2018 Oct}, pages = {675-684}, abstract = {

BACKGROUND: Brain arteriovenous malformations (BAVM) represent a congenital anomaly of the cerebral vessels with a prevalence of 10-18/100 000. BAVM is the leading aetiology of intracranial haemorrhage in children. Our objective was to identify gene variants potentially contributing to disease and to better define the molecular aetiology underlying non-syndromic sporadic BAVM.

METHODS: We performed whole-exome trio sequencing of 100 unrelated families with a clinically uniform BAVM phenotype. Pathogenic variants were then studied in vivo using a transgenic zebrafish model.

RESULTS: We identified four pathogenic heterozygous variants in four patients, including one in the established BAVM-related gene, , and three damaging variants in novel candidate genes: , and , which we then functionally validated in zebrafish. In addition, eight likely pathogenic heterozygous variants (, and ) were identified in eight patients, and 16 patients carried one or more variants of uncertain significance. Potential oligogenic inheritance ( with , with and with ) was identified in three patients. Regulation of sma- and mad-related proteins (SMADs) (involved in bone morphogenic protein (BMP)/transforming growth factor beta (TGF-β) signalling) and vascular endothelial growth factor (VEGF)/vascular endotheliual growth factor recepter 2 (VEGFR2) binding and activity (affecting the VEGF signalling pathway) were the most significantly affected biological process involved in the pathogenesis of BAVM.

CONCLUSIONS: Our study highlights the specific role of BMP/TGF-β and VEGF/VEGFR signalling in the aetiology of BAVM and the efficiency of intensive parallel sequencing in the challenging context of genetically heterogeneous paradigm.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2017-105224}, author = {Wang, Kun and Zhao, Sen and Liu, Bowen and Zhang, Qianqian and Li, Yaqi and Liu, Jiaqi and Shen, Yan and Ding, Xinghuan and Lin, Jiachen and Wu, Yong and Yan, Zihui and Chen, Jia and Li, Xiaoxin and Song, Xiaofei and Niu, Yuchen and Liu, Jian and Chen, Weisheng and Ming, Yue and Du, Renqian and Chen, Cong and Long, Bo and Zhang, Yisen and Tong, Xiangjun and Zhang, Shuyang and Posey, Jennifer E and Zhang, Bo and Wu, Zhihong and Wythe, Joshua D and Liu, Pengfei and Lupski, James R and Yang, Xinjian and Wu, Nan} } @article {617, title = {Predicting human genes susceptible to genomic instability associated with /-mediated rearrangements.}, journal = {Genome Res}, volume = {28}, year = {2018}, month = {2018 08}, pages = {1228-1242}, abstract = {

elements, the short interspersed element numbering more than 1 million copies per human genome, can mediate the formation of copy number variants (CNVs) between substrate pairs. These /-mediated rearrangements (AAMRs) can result in pathogenic variants that cause diseases. To investigate the impact of AAMR on gene variation and human health, we first characterized s that are involved in mediating CNVs (CNV-s) and observed that these s tend to be evolutionarily younger. We then computationally generated, with the assistance of a supercomputer, a test data set consisting of 78 million pairs and predicted \~{}18\% of them are potentially susceptible to AAMR. We further determined the relative risk of AAMR in 12,074 OMIM genes using the count of predicted CNV- pairs and experimentally validated the predictions with 89 samples selected by correlating predicted hotspots with a database of CNVs identified by clinical chromosomal microarrays (CMAs) on the genomes of approximately 54,000 subjects. We fine-mapped 47 duplications, 40 deletions, and two complex rearrangements and examined a total of 52 breakpoint junctions of simple CNVs. Overall, 94\% of the candidate breakpoints were at least partially mediated. We successfully predicted all (100\%) of pairs that mediated deletions ( = 21) and achieved an 87\% positive predictive value overall when including AAMR-generated deletions and duplications. We provided a tool, AluAluCNVpredictor, for assessing AAMR hotspots and their role in human disease. These results demonstrate the utility of our predictive model and provide insights into the genomic features and molecular mechanisms underlying AAMR.

}, keywords = {Alu Elements, DNA Copy Number Variations, Gene Duplication, Genome, Human, Genomic Instability, Humans, Sequence Deletion}, issn = {1549-5469}, doi = {10.1101/gr.229401.117}, author = {Song, Xiaofei and Beck, Christine R and Du, Renqian and Campbell, Ian M and Coban-Akdemir, Zeynep and Gu, Shen and Breman, Amy M and Stankiewicz, Pawel and Ira, Grzegorz and Shaw, Chad A and Lupski, James R} }