HOME > RESEARCH > Publications
Publications
Wu N, Ming X, Xiao J, et al. TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med. 2015;372(4):341-350. doi:10.1056/NEJMoa1406829
Background: Congenital scoliosis is a common type of vertebral malformation. Genetic susceptibility has been implicated in congenital scoliosis.
Methods: We evaluated 161 Han Chinese persons with sporadic congenital scoliosis, 166 Han Chinese controls, and 2 pedigrees, family members of which had a 16p11.2 deletion, using comparative genomic hybridization, quantitative polymerase-chain-reaction analysis, and DNA sequencing. We carried out tests of replication using an additional series of 76 Han Chinese persons with congenital scoliosis and a multicenter series of 42 persons with 16p11.2 deletions.
Results: We identified a total of 17 heterozygous TBX6 null mutations in the 161 persons with sporadic congenital scoliosis (11%); we did not observe any null mutations in TBX6 in 166 controls (P<3.8×10(-6)). These null alleles include copy-number variants (12 instances of a 16p11.2 deletion affecting TBX6) and single-nucleotide variants (1 nonsense and 4 frame-shift mutations). However, the discordant intrafamilial phenotypes of 16p11.2 deletion carriers suggest that heterozygous TBX6 null mutation is insufficient to cause congenital scoliosis. We went on to identify a common TBX6 haplotype as the second risk allele in all 17 carriers of TBX6 null mutations (P<1.1×10(-6)). Replication studies involving additional persons with congenital scoliosis who carried a deletion affecting TBX6 confirmed this compound inheritance model. In vitro functional assays suggested that the risk haplotype is a hypomorphic allele. Hemivertebrae are characteristic of TBX6-associated congenital scoliosis.
Conclusions: Compound inheritance of a rare null mutation and a hypomorphic allele of TBX6 accounted for up to 11% of congenital scoliosis cases in the series that we analyzed. (Funded by the National Basic Research Program of China and others.).
Liu J, Zhao H, Zheng Y, et al. DrABC: deep learning accurately predicts germline pathogenic mutation status in breast cancer patients based on phenotype data. Genome Med. 2022;14(1):21. Published 2022 Feb 25. doi:10.1186/s13073-022-01027-9
Background: Identifying breast cancer patients with DNA repair pathway-related germline pathogenic variants (GPVs) is important for effectively employing systemic treatment strategies and risk-reducing interventions. However, current criteria and risk prediction models for prioritizing genetic testing among breast cancer patients do not meet the demands of clinical practice due to insufficient accuracy.
Methods: The study population comprised 3041 breast cancer patients enrolled from seven hospitals between October 2017 and 11 August 2019, who underwent germline genetic testing of 50 cancer predisposition genes (CPGs). Associations among GPVs in different CPGs and endophenotypes were evaluated using a case-control analysis. A phenotype-based GPV risk prediction model named DNA-repair Associated Breast Cancer (DrABC) was developed based on hierarchical neural network architecture and validated in an independent multicenter cohort. The predictive performance of DrABC was compared with currently used models including BRCAPRO, BOADICEA, Myriad, PENN II, and the NCCN criteria.
Results: In total, 332 (11.3%) patients harbored GPVs in CPGs, including 134 (4.6%) in BRCA2, 131 (4.5%) in BRCA1, 33 (1.1%) in PALB2, and 37 (1.3%) in other CPGs. GPVs in CPGs were associated with distinct endophenotypes including the age at diagnosis, cancer history, family cancer history, and pathological characteristics. We developed a DrABC model to predict the risk of GPV carrier status in BRCA1/2 and other important CPGs. In predicting GPVs in BRCA1/2, the performance of DrABC (AUC = 0.79 [95% CI, 0.74-0.85], sensitivity = 82.1%, specificity = 63.1% in the independent validation cohort) was better than that of previous models (AUC range = 0.57-0.70). In predicting GPVs in any CPG, DrABC (AUC = 0.74 [95% CI, 0.69-0.79], sensitivity = 83.8%, specificity = 51.3% in the independent validation cohort) was also superior to previous models in their current versions (AUC range = 0.55-0.65). After training these previous models with the Chinese-specific dataset, DrABC still outperformed all other methods except for BOADICEA, which was the only previous model with the inclusion of pathological features. The DrABC model also showed higher sensitivity and specificity than the NCCN criteria in the multi-center validation cohort (83.8% and 51.3% vs. 78.8% and 31.2%, respectively, in predicting GPVs in any CPG).
Conclusions: By considering the distinct endophenotypes associated with different CPGs in breast cancer patients, a phenotype-driven prediction model based on hierarchical neural network architecture was created for identification of hereditary breast cancer. The model achieved superior performance in identifying GPV carriers among Chinese breast cancer patients.
Chen Z, Zheng Y, Yang Y, et al. PhenoApt leverages clinical expertise to prioritize candidate genes via machine learning. Am J Hum Genet. 2022;109(2):270-281. doi:10.1016/j.ajhg.2021.12.008
In recent years, exome sequencing (ES) has shown great utility in the diagnoses of Mendelian disorders. However, after rigorous filtering, a typical ES analysis still involves the interpretation of hundreds of variants, which greatly hinders the rapid identification of causative genes. Since the interpretations of ES data require comprehensive clinical analyses, taking clinical expertise into consideration can speed the molecular diagnoses of Mendelian disorders. To leverage clinical expertise to prioritize candidate genes, we developed PhenoApt, a phenotype-driven gene prioritization tool that allows users to assign a customized weight to each phenotype, via a machine-learning algorithm. Using the ability to rank causative genes in top-10 lists as an evaluation metric, baseline analysis demonstrated that PhenoApt outperformed previous phenotype-driven gene prioritization tools by a relative increase of 22.7%–140.0% in three independent, real-world, multi-center cohorts (cohort 1, n = 185; cohort 2, n = 784; and cohort 3, n = 208). Additional trials showed that, by adding weights to clinical indications, which should be explained by the causative gene, PhenoApt performance was improved by a relative increase of 37.3% in cohort 2 (n = 471) and 21.4% in cohort 3 (n = 208). Moreover, PhenoApt could assign an intrinsic weight to each phenotype based on the likelihood of its being a Mendelian trait using term frequency-inverse document frequency techniques. When clinical indications were assigned with intrinsic weights, PhenoApt performance was improved by a relative increase of 23.7% in cohort 2 and 15.5% in cohort 3. For the integration of PhenoApt into clinical practice, we developed a user-friendly website and a command-line tool.
Chen N, Zhao S, Jolly A, et al. Perturbations of genes essential for Müllerian duct and Wölffian duct development in Mayer-Rokitansky-Küster-Hauser syndrome. Am J Hum Genet. 2021;108(2):337-345. doi:10.1016/j.ajhg.2020.12.014
Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is associated with congenital absence of the uterus, cervix, and the upper part of the vagina; it is a sex-limited trait. Disrupted development of the Müllerian ducts (MD)/Wölffian ducts (WD) through multifactorial mechanisms has been proposed to underlie MRKHS. In this study, exome sequencing (ES) was performed on a Chinese discovery cohort (442 affected subjects and 941 female control subjects) and a replication MRKHS cohort (150 affected subjects of mixed ethnicity from North America, South America, and Europe). Phenotypic follow-up of the female reproductive system was performed on an additional cohort of PAX8-associated congenital hypothyroidism (CH) (n = 5, Chinese). By analyzing 19 candidate genes essential for MD/WD development, we identified 12 likely gene-disrupting (LGD) variants in 7 genes: PAX8 (n = 4), BMP4 (n = 2), BMP7 (n = 2), TBX6 (n = 1), HOXA10 (n = 1), EMX2 (n = 1), and WNT9B (n = 1), while LGD variants in these genes were not detected in control samples (p = 1.27E−06). Interestingly, a sex-limited penetrance with paternal inheritance was observed in multiple families. One additional PAX8 LGD variant from the replication cohort and two missense variants from both cohorts were revealed to cause loss-of-function of the protein. From the PAX8-associated CH cohort, we identified one individual presenting a syndromic condition characterized by CH and MRKHS (CH-MRKHS). Our study demonstrates the comprehensive utilization of knowledge from developmental biology toward elucidating genetic perturbations, i.e., rare pathogenic alleles involving the same loci, contributing to human birth defects.
Wang K, Zhao S, Xie Z, et al. Exome-wide Analysis of De Novo and Rare Genetic Variants in Patients With Brain Arteriovenous Malformation [published online ahead of print, 2022 Feb 28]. Neurology. 2022;10.1212/WNL.0000000000200114. doi:10.1212/WNL.0000000000200114
Background and objectives: Brain arteriovenous malformation (bAVM) is a congenital disorder and a leading cause of hemorrhagic stroke. Germline genetic variants play an essential role in the pathogenesis of brain arteriovenous malformation. However, the biological relevance of the disease-associated genes identified in previous studies is elusive. In this study, we aim to systematically investigate the contribution of germline variants to bAVM and explore the critical molecular pathways underlying the pathogenesis of bAVM.
Methods: Probands with sporadic bAVM were consecutively recruited into this study from November 2015 to November 2018 and underwent exome sequencing. The controls were aggregated from individuals who were not known to have vascular malformation and underwent exome sequencing for clinical or research purposes. The retained control dataset included 4609 individuals, including 251 individuals with parental samples sequenced. We firstly compared de novo variants in cases and controls and performed a pathway enrichment analysis. A gene-based rare variant association analysis was then performed to identify genes whose variants were significantly enriched in cases.
Results: We collected an exome-sequenced bAVM cohort consisting of 152 trios and 40 singletons. By firstly focusing on de novo variants, we observed a significant mutational burden of de novo likely gene-disrupting variants in cases versus controls. By performing a pathway enrichment analysis of all nonsynonymous de novo variants identified in cases, we found the angiopoietin-like protein 8 (ANGPTL8) regulatory pathway to be significantly enriched in patients with bAVM. Through an exome-wide rare variant association analysis utilizing 4394 in-house exome data as controls, we identified SLC19A3 as a disease-associated gene for bAVM. In addition, we found that the SLC19A3 variants in cases are preferably located at the N’ side of the SLC19A3 protein. These findings implicate a phenotypic extension of SLC19A3-related disorders with a domain-specific effect.
Discussion: This study provides insights into the biological basis of bAVM by identifying novel molecular pathways and candidate genes.
Zhao S, Zhang Y, Hallgrimsdottir S, et al. Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders. NPJ Genom Med. 2022;7(1):11. Published 2022 Feb 15. doi:10.1038/s41525-021-00273-x
Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.
Bao S, Hu T, Liu J, et al. Genomic instability-derived plasma extracellular vesicle-microRNA signature as a minimally invasive predictor of risk and unfavorable prognosis in breast cancer. J Nanobiotechnology. 2021;19(1):22. Published 2021 Jan 12. doi:10.1186/s12951-020-00767-3
Yang Y, Zhao S, Zhang Y, et al. Mutational burden and potential oligogenic model of TBX6-mediated genes in congenital scoliosis. Molecular Genetics & Genomic Medicine, 2020；e1453.
Shao J, Zhao S, Yan Z, et al. A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia [J]. BMC medical genetics, 2020；21(1): 115
Li Z, Zhao S, Cai S, et al. The mutational burden and oligogenic inheritance in Klippel-Feil syndrome. BMC Musculoskelet Disord, 2020;21(1):220
Wang L, Zhang Y, Zhao S, et al. Estrogen Receptors (ESRs) Mutations in Adolescent Idiopathic Scoliosis: A Cross-Sectional Study. Med Sci Monit, 2020；26:e921611-1–e921611-7
Li Y, Li C, Wu N, et al. Demographic, clinical, and scintigraphic comparison of patients affected by palmoplantar pustulosis and severe acne: a retrospective study [J]. Clinical rheumatology, 2020, 39(6): 1989-1996
Wu N, Zhang Z, Zhou X, et al. Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia [J]. J Cell Mol Med, 2020, 24(9): 4931-4943
Yang N, Wu N, Dong S, et al. Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome [J]. Kidney international, 2020；98(4):1020-1030
Yang Y, Zhao S, Zhang Y, et al. Mutational burden and potential oligogenic model of TBX6-mediated genes in congenital scoliosis. Molecular Genetics & Genomic Medicine, 2020；e1453.
Shao J, Zhao S, Yan Z, et al. A novel COMP mutation in a Chinese family with multiple epiphyseal dysplasia [J]. BMC medical genetics, 2020；21(1): 115
Li Z, Zhao S, Cai S, et al.The mutational burden and oligogenic inheritance in Klippel-Feil syndrome. BMC Musculoskelet Disord, 2020;21(1):220
Wang L, Zhang Y, Zhao S, et al. Estrogen Receptors (ESRs) Mutations in Adolescent Idiopathic Scoliosis: A Cross-Sectional Study. Med Sci Monit, 2020；26:e921611-1–e921611-7
Li Y, Li C, Wu N, et al. Demographic, clinical, and scintigraphic comparison of patients affected by palmoplantar pustulosis and severe acne: a retrospective study [J]. Clinical rheumatology, 2020, 39(6): 1989-1996
Wu N, Zhao Y, Tao W, et al. A single cohort, open-label study of the efficacy of pamidronate for palmoplantar pustulosis in synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome. Clin Exp Rheumatol, 2020, Jun 15
Wu N, Zhang Z, Zhou X, et al. Mutational landscape and genetic signatures of cell-free DNA in tumour-induced osteomalacia [J]. J Cell Mol Med, 2020, 24(9): 4931-4943
Chen Y., Liu Z., Chen J., Zuo Y., Liu S., Chen W., Liu G., Qiu G., Giampietro P.F., Wu N.*, and Wu Z.*, The genetic landscape and clinical implications of vertebral anomalies in VACTERL association. J Med Genet, 2016. 53(7): p.431-7.
Yang N, Wu N, Dong S, et al. Human and mouse studies establish TBX6 in Mendelian CAKUT and as a potential driver of kidney defects associated with the 16p11.2 microdeletion syndrome [J]. Kidney international, 2020；98(4):1020-1030
For a complete list of publications
Please find at: ((((Nan Wu[Author]) OR Zhihong Wu[Author]) OR Guixing Qiu[Author])) AND peking union medical college hospital