Thesis Type: Doctorate
Institution Of The Thesis: Istanbul University, Health Sciences Institute, İstanbul Tıp Fakültesi Bölümü, Turkey
Approval Date: 2023
Thesis Language: Turkish
Student: SOMAYYEH HEIDARGHOLIZADEH
Principal Supervisor (For Co-Supervisor Theses): Birsen Karaman
Co-Supervisor: Çağrı Güleç
Abstract:
A thin skeletal muscle located between the abdominal and the thoracic cavity,
the diaphragm, is necessary for the continuity of respiratory function. Congenital
Diaphragmatic Hernias (CDH) that occur as a result of defects in the development of
the diaphragm is identified as a severe anomaly with high mortality and requiring
surgical intervention. CDH, could be as an isolated or syndromic types and is
characterized by herniation of abdominal contents into the thoracic cavity that may
result in pulmonary hypoplasia or pulmonary hypertension.
CDH, where genetic and environmental factors play a role in its etiology, has
been shown to be associated with numerous chromosomal anomalies, copy number
variations (CNVs) and gene sequence variants, although these changes were insufficient
to explain the etiology of all CDH cases. It is thought that more genes and factors play a
role in the etiology of CDH and studies conducted for this purpose have shown the
importance of retinoic acid (RA) signaling pathway and related genes in particular.
However, because of many other processes such as cell migration, cytoskeleton
organization, and myogenesis involved in diaphragmatic development, genes with
pathogenic variants responsible for CDH are not limited to RA signaling pathway
genes. It is expected that the use of methods such as NGS-based whole-exome
sequencing (WES) will be effective in investigation of the genetic basis of CDH, in
which many genes are thought to play a role in its etiology.
In order to identify new candidate genes responsible for CDH, within the scope
of this project, trio-WES analysis was performed in eight fetuses and their parents, and
solo-WES analysis was performed in ten fetus with excluded CNVs by chromosome
analysis and a-CGH study. As a result of the bioinformatics analysis, pathogenic
variants have been identified in the genes that were directly associated with CDH
(NR2F2, ZFPM2, ARID1A, CREBBP, PLAT, POGZ and RARB) and in candidate genes
that their association with CDH may be found based on their functions, databases and
literature data (CDKL4, STAB2, NEIL2, SETD5, TAF4, ZBTB38, ZNF423, COL11A1,
PCSK5 and RBM8A).
In summary, the results of the project study support the notion that a single gene
or variant is not responsible for the majority of CDH cases. The functional effects of the
new variants detected in different genes in our cases and their clinical relevance should
be supported by functional or animal model studies. However, the findings of our study
have the potential to become a resource for similar studies in the future and thus
contribute to the literature on the genes and the variants that play a role in the etiology
of CDH.