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. 2022 Oct;188(10):2958-2968.
doi: 10.1002/ajmg.a.62919. Epub 2022 Jul 29.

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

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

Amy Hardcastle et al. Am J Med Genet A. 2022 Oct.

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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Figures

Figure 1.
Figure 1.. Genes identified in this study are more similar to a set of 31 genes known to cause CDH than would be expected by chance.
Box plots generated based on the CDH-specific pathogenicity scores of, 1) the 31 known CDH genes used to train our machine learning algorithm (Callaway et al., 2018), 2) genes for which there is sufficient evidence to support a phenotype expansion involving CDH (Table 1) and, 3) genes for which there is currently insufficient evidence to support a phenotype expansion involving CDH (Tables 2 and 3). As expected, the medians of the genes listed in Table 1 (78.7%), Table 2 (81.5%) and Table 3 (76.4%) were lower that of the training genes (99.8%) but exceeded the median for all RefSeq genes (50%; chance) represented by the dashed line. This indicates that each of these groups are enriched for genes that are similar to the 31 known CDH genes in the training set.
See this image and copyright information in PMC

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