Am J Med Genet A
. 2022 Jul 29.
doi: 10.1002/ajmg.a.62919. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/35904974/
Identifying phenotypic expansions for congenital diaphragmatic hernia plus (CDH+) using DECIPHER data
Amy Hardcastle 1, Aliska M Berry 2, Ian M Campbell 3, Xiaonan Zhao 2 4, Pengfei Liu 2 4, Amanda E Gerard 2 5, Jill A Rosenfeld 2, Saumya D Sisoudiya 2, Andres Hernandez-Garcia 2, Sara Loddo 6, Silvia Di Tommaso 6, Antonio Novelli 6, Maria L Dentici 7 8, Rossella Capolino 7 8, Maria C Digilio 7 8, Ludovico Graziani 8 9, Cecilie F Rustad 10, Katherine Neas 11, Giovanni B Ferrero 12, Alfredo Brusco 13 14, Eleonora Di Gregorio 14, Diana Wellesley 15 16, Claire Beneteau 17, Madeleine Joubert 17, Kris Van Den Bogaert 18, Anneleen Boogaerts 18, Dominic J McMullan 19, John Dean 20, Maria G Giuffrida 21, Laura Bernardini 21, Vinod Varghese 22, Nora L Shannon 23, Rachel E Harrison 23, Wayne W K Lam 24, Shane McKee 25, Peter D Turnpenny 26, Trevor Cole 27, Jenny Morton 27, Jacqueline Eason 23, Marilyn C Jones 28, Rebecca Hall 29, Michael Wright 29, Karen Horridge 30, Chad A Shaw 2, Wendy K Chung 31 32, Daryl A Scott 2 5 33
- PMID: 35904974
- DOI: 10.1002/ajmg.a.62919
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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