Genetic Basis of Non Syndromic Congenital Diaphragmatic Hernia

Genetic Basis of Non Syndromic Congenital Diaphragmatic Hernia

In isolated congenital diaphragmatic hernia (CDH), recurrent risk is low suggesting the occurrence of novo mutations (dominant or recessive). Our objective is to test this hypothesis by combining the search for pathogenic genomic alteration and intragenic mutations through whole exome sequencing in a homogenous group of patients.

To elucidate the genetic basis of non syndromic congenital diaphragmatic hernia in a sub group of individuals with similar phenotype: Isolated CDH presenting with postero-lateral-left diaphragmatic defect with good perinatal outcome (n=16) To establish the prevalence of the identified gene(s) in a cohort of identical patients (n=30)

Two complementary approaches will be used:

• Search for pathogenic genomic alterations using microarrays (~2.106 markers (SNP and CNV) in 16 trios (affected child and 2 parents).
• Sequencing of the whole exome from patient genomic DNA (n=16)
• Selection of unknown or very rare variants according to different criteria: recessive or dominant model, prediction of their pathogenicity, filtered on genes already known in CDH or involved in diaphragmatic development and non annotated CNV or variants of new gene(s) shared by different patients.
• Variants will be validated by Sanger sequencing (for intragenic variants) or quantitative PCR (for CNV) on CDH cases and their parents as well as their absence on 100 controls.

Inclusion Criteria:

• Families with one (or more) non syndromic CDH child
• Signed consent form

Exclusion Criteria:

• Syndromic CDH or associated with a known karyotype anomaly
• No signed consent form
• Not affiliated to French social security