Research: Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data

Am J Med Genet A

. 2022 Jul 29.

 doi: 10.1002/ajmg.a.62919. Online ahead of print.

Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data

Amy Hardcastle 1Aliska M Berry 2Ian M Campbell 3Xiaonan Zhao 2 4Pengfei Liu 2 4Amanda E Gerard 2 5Jill A Rosenfeld 2Saumya D Sisoudiya 2Andres Hernandez-Garcia 2Sara Loddo 6Silvia Di Tommaso 6Antonio Novelli 6Maria L Dentici 7 8Rossella Capolino 7 8Maria C Digilio 7 8Ludovico Graziani 8 9Cecilie F Rustad 10Katherine Neas 11Giovanni B Ferrero 12Alfredo Brusco 13 14Eleonora Di Gregorio 14Diana Wellesley 15 16Claire Beneteau 17Madeleine Joubert 17Kris Van Den Bogaert 18Anneleen Boogaerts 18Dominic J McMullan 19John Dean 20Maria G Giuffrida 21Laura Bernardini 21Vinod Varghese 22Nora L Shannon 23Rachel E Harrison 23Wayne W K Lam 24Shane McKee 25Peter D Turnpenny 26Trevor Cole 27Jenny Morton 27Jacqueline Eason 23Marilyn C Jones 28Rebecca Hall 29Michael Wright 29Karen Horridge 30Chad A Shaw 2Wendy K Chung 31 32Daryl A Scott 2 5 33

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Congenital diaphragmatic hernia (CDH) can occur in isolation or in conjunction with other birth defects (CDH+). A molecular etiology can only be identified in a subset of CDH cases. This is due, in part, to an incomplete understanding of the genes that contribute to diaphragm development. Here, we used clinical and molecular data from 36 individuals with CDH+ who are cataloged in the DECIPHER database to identify genes that may play a role in diaphragm development and to discover new phenotypic expansions. Among this group, we identified individuals who carried putatively deleterious sequence or copy number variants affecting CREBBP, SMARCA4, UBA2, and USP9X. The role of these genes in diaphragm development was supported by their expression in the developing mouse diaphragm, their similarity to known CDH genes using data from a previously published and validated machine learning algorithm, and/or the presence of CDH in other individuals with their associated genetic disorders. Our results demonstrate how data from DECIPHER, and other public databases, can be used to identify new phenotypic expansions and suggest that CREBBP, SMARCA4, UBA2, and USP9X play a role in diaphragm development.

Keywords: CREBBP; DECIPHER database; SMARCA4; UBA2; USP9X; congenital diaphragmatic hernia.

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