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

Affiliations expand

• PMID: 35904974
• DOI: 10.1002/ajmg.a.62919

Abstract

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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