@article {983,
	title = {Perturbations of genes essential for M{\"u}llerian duct and W{\"o}lffian duct development in Mayer-Rokitansky-K{\"u}ster-Hauser syndrome.},
	journal = {Am J Hum Genet},
	volume = {108},
	year = {2021},
	month = {2021 02 04},
	pages = {337-345},
	abstract = {<p>Mayer-Rokitansky-K{\"u}ster-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 M{\"u}llerian ducts (MD)/W{\"o}lffian 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.</p>},
	keywords = {46, XX Disorders of Sex Development, Adult, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein 7, Codon, Nonsense, Congenital Abnormalities, Female, Genetic Association Studies, Genetic Pleiotropy, Homeobox A10 Proteins, Homeodomain Proteins, Humans, Mullerian Ducts, Mutation, Paternal Inheritance, PAX8 Transcription Factor, Penetrance, T-Box Domain Proteins, Transcription Factors, Wnt Proteins, Wolffian Ducts},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2020.12.014},
	author = {Chen, Na and Zhao, Sen and Jolly, Angad and Wang, Lianlei and Pan, Hongxin and Yuan, Jian and Chen, Shaoke and Koch, Andr{\'e} and Ma, Congcong and Tian, Weijie and Jia, Ziqi and Kang, Jia and Zhao, Lina and Qin, Chenglu and Fan, Xin and Rall, Katharina and Coban-Akdemir, Zeynep and Chen, Zefu and Jhangiani, Shalini and Liang, Ze and Niu, Yuchen and Li, Xiaoxin and Yan, Zihui and Wu, Yong and Dong, Shuangshuang and Song, Chengcheng and Qiu, Guixing and Zhang, Shuyang and Liu, Pengfei and Posey, Jennifer E and Zhang, Feng and Luo, Guangnan and Wu, Zhihong and Su, Jianzhong and Zhang, Jianguo and Chen, Eugenia Y and Rouskas, Konstantinos and Glentis, Stavros and Bacopoulou, Flora and Deligeoroglou, Efthymios and Chrousos, George and Lyonnet, Stanislas and Polak, Michel and Rosenberg, Carla and Dingeldein, Irene and Bonilla, Ximena and Borel, Christelle and Gibbs, Richard A and Dietrich, Jennifer E and Dimas, Antigone S and Antonarakis, Stylianos E and Brucker, Sara Y and Lupski, James R and Wu, Nan and Zhu, Lan}
}
@article {576,
	title = {Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway.},
	journal = {Am J Hum Genet},
	volume = {104},
	year = {2019},
	month = {2019 02 07},
	pages = {213-228},
	abstract = {<p>Primary defects in lung branching morphogenesis, resulting in neonatal lethal pulmonary hypoplasias, are incompletely understood. To elucidate the pathogenetics of human lung development, we studied a unique collection of samples obtained from deceased individuals with clinically and histopathologically diagnosed interstitial neonatal lung disorders: acinar dysplasia (n = 14), congenital alveolar dysplasia (n = 2), and other lethal lung hypoplasias (n = 10). We identified rare heterozygous copy-number variant deletions or single-nucleotide variants (SNVs) involving TBX4 (n = 8 and n = 2, respectively) or FGF10 (n = 2 and n = 2, respectively) in 16/26 (61\%) individuals. In addition to TBX4, the overlapping \~{}2 Mb recurrent and nonrecurrent deletions at 17q23.1q23.2 identified in seven individuals with lung hypoplasia also remove a lung-specific enhancer region. Individuals with coding variants involving either TBX4 or FGF10 also harbored at least one non-coding SNV in the predicted lung-specific enhancer region, which was absent in 13 control individuals with the overlapping deletions but without any structural lung anomalies. The occurrence of rare coding variants involving TBX4 or FGF10 with the putative hypomorphic non-coding SNVs implies a complex compound inheritance of these pulmonary hypoplasias. Moreover, they support the importance of TBX4-FGF10-FGFR2 epithelial-mesenchymal signaling in human lung organogenesis and help to explain the histopathological continuum observed in these rare lethal developmental disorders of the lung.</p>},
	keywords = {DNA Copy Number Variations, Female, Fibroblast Growth Factor 10, Gene Expression Regulation, Gestational Age, Humans, Infant, Newborn, Infant, Newborn, Diseases, Lung, Lung Diseases, Male, Maternal Inheritance, Organogenesis, Paternal Inheritance, Pedigree, Polymorphism, Single Nucleotide, Receptor, Fibroblast Growth Factor, Type 2, Signal Transduction, T-Box Domain Proteins},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2018.12.010},
	author = {Karolak, Justyna A and Vincent, Marie and Deutsch, Gail and Gambin, Tomasz and Cogn{\'e}, Benjamin and Pichon, Olivier and Vetrini, Francesco and Mefford, Heather C and Dines, Jennifer N and Golden-Grant, Katie and Dipple, Katrina and Freed, Amanda S and Leppig, Kathleen A and Dishop, Megan and Mowat, David and Bennetts, Bruce and Gifford, Andrew J and Weber, Martin A and Lee, Anna F and Boerkoel, Cornelius F and Bartell, Tina M and Ward-Melver, Catherine and Besnard, Thomas and Petit, Florence and Bache, Iben and T{\"u}mer, Zeynep and Denis-Musquer, Marie and Joubert, Madeleine and Martinovic, Jelena and B{\'e}n{\'e}teau, Claire and Molin, Arnaud and Carles, Dominique and Andr{\'e}, Gwenaelle and Bieth, Eric and Chassaing, Nicolas and Devisme, Louise and Chalabreysse, Lara and Pasquier, Laurent and Secq, V{\'e}ronique and Don, Massimiliano and Orsaria, Maria and Missirian, Chantal and Mortreux, J{\'e}r{\'e}mie and Sanlaville, Damien and Pons, Linda and K{\"u}ry, S{\'e}bastien and B{\'e}zieau, St{\'e}phane and Liet, Jean-Michel and Joram, Nicolas and Bihou{\'e}e, Tiphaine and Scott, Daryl A and Brown, Chester W and Scaglia, Fernando and Tsai, Anne Chun-Hui and Grange, Dorothy K and Phillips, John A and Pfotenhauer, Jean P and Jhangiani, Shalini N and Gonzaga-Jauregui, Claudia G and Chung, Wendy K and Schauer, Galen M and Lipson, Mark H and Mercer, Catherine L and van Haeringen, Arie and Liu, Qian and Popek, Edwina and Coban Akdemir, Zeynep H and Lupski, James R and Szafranski, Przemyslaw and Isidor, Bertrand and Le Caignec, Cedric and Stankiewicz, Pawe{\l}}
}
