Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus

Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus. Sy, M. R., Chauhan, J., Prescott, K., Imam, A., Kraus, A., Beleza, A., Salkeld, L., Hosdurga, S., Parker, M., Vasudevan, P., Islam, L., Goel, H., Bain, N., Park, S., Mohammed, S., Dieterich, K., Coutton, C., Satre, V., Vieville, G., Donaldson, A., Beneteau, C., Ghoumid, J., Van Den Bogaert, K., Boogaerts, A., Boudry, E., Vanlerberghe, C., Petit, F., Bernardini, L., Torres, B., Mattina, T., Carli, D., Mandrile, G., Pinelli, M., Brunetti-Pierri, N., Neas, K., Beddow, R., Tørring, P. M., Faletra, F., Spedicati, B., Gasparini, P., Mussa, A., Ferrero, G. B., Lampe, A., Lam, W., Bi, W., Bacino, C. A., Kuwahara, A., Bush, J. O., Zhao, X., Luna, P. N., Shaw, C. A., Rosenfeld, J. A., & Scott, D. A. American Journal of Medical Genetics. Part A, 188(12):3492–3504, December, 2022.

Paper doi abstract bibtex

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.

@article{sy_exome_2022,
	title = {Exome sequencing efficacy and phenotypic expansions involving esophageal atresia/tracheoesophageal fistula plus},
	volume = {188},
	issn = {1552-4833},
	url = {https://pubmed.ncbi.nlm.nih.gov/36135330/},
	doi = {10.1002/ajmg.a.62976},
	abstract = {Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16\% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF.},
	language = {eng},
	number = {12},
	journal = {American Journal of Medical Genetics. Part A},
	author = {Sy, Mary R. and Chauhan, Jaynee and Prescott, Katrina and Imam, Aliza and Kraus, Alison and Beleza, Ana and Salkeld, Lee and Hosdurga, Saraswati and Parker, Michael and Vasudevan, Pradeep and Islam, Lily and Goel, Himanshu and Bain, Nicole and Park, Soo-Mi and Mohammed, Shehla and Dieterich, Klaus and Coutton, Charles and Satre, Véronique and Vieville, Gaëlle and Donaldson, Alan and Beneteau, Claire and Ghoumid, Jamal and Van Den Bogaert, Kris and Boogaerts, Anneleen and Boudry, Elise and Vanlerberghe, Clémence and Petit, Florence and Bernardini, Laura and Torres, Barbara and Mattina, Teresa and Carli, Diana and Mandrile, Giorgia and Pinelli, Michele and Brunetti-Pierri, Nicola and Neas, Katherine and Beddow, Rachel and Tørring, Pernille M. and Faletra, Flavio and Spedicati, Beatrice and Gasparini, Paolo and Mussa, Alessandro and Ferrero, Giovanni Battista and Lampe, Anne and Lam, Wayne and Bi, Weimin and Bacino, Carlos A. and Kuwahara, Akela and Bush, Jeffrey O. and Zhao, Xiaonan and Luna, Pamela N. and Shaw, Chad A. and Rosenfeld, Jill A. and Scott, Daryl A.},
	month = dec,
	year = {2022},
	keywords = {Esophageal Atresia, Exome, Exome Sequencing, Fanconi anemia, Humans, NRXN1, TCF4, Tracheoesophageal Fistula, esophageal atresia, exome sequencing, tracheoesophageal fistula},
	pages = {3492--3504},
}

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