Novel genetic associations and range of phenotypes in Deciphering Developmental Disorders (DDD) study participants with hypospadias

Gazdagh, Gabriella Erika (2021) Novel genetic associations and range of phenotypes in Deciphering Developmental Disorders (DDD) study participants with hypospadias. MD thesis, University of Glasgow.

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Hypospadias is characterised by a displacement of the urethral orifice affecting approximately 1 in 200-300 boys and may be an isolated finding or occur together with other developmental problems including learning disability. Its aetiology has been investigated for decades with environmental, endocrine and genetic factors felt to contribute to its development. Current knowledge regarding the genetic causes of hypospadias is scarce and in at least half of the hypospadias cases no molecular diagnosis is established. The UK-wide Deciphering Developmental Disorders (DDD) Study enabled clinicians to undertake complementary analysis projects (CAPs) using phenotype data collected from recruiting clinical geneticists and genotype information generated by the DDD Study researchers.
The aims of this study were to detect new and known variants in genes already linked to hypospadias and to explore the possibility of discovering new genetic associations with this condition. Additional aims were to describe the frequency of genital abnormalities in DDD participants and to describe associated clinical features while investigating whether there is a common combination of features observed in this group of patients. The hypothesis was that VCF file re-analysis of selected DDD participants with similar constellation of associated clinical features would facilitate identification of potentially causative variants in the same gene or genetic pathway.
Investigations were started with a preliminary analysis describing the range and prevalence of genital abnormalities in DDD participants and assessing reported variants in the first 1133 families recruited into the DDD study. This analysis showed that genital abnormalities are present in approximately 6% of DDD patients, with hypospadias being the second most common genital problem. A review of reported variants in the first 1133 families demonstrated that it is possible to extend the clinical spectrum of known syndromes by reporting associated genital abnormalities. In order to select a group of patients with the highest reporter certainty, individuals with hypospadias were chosen as the study group.
An analysis of associated features of DDD participants with hypospadias compared to those without hypospadias identified that cardiovascular and growth abnormalities are more likely to occur in individuals with hypospadias. To remove neurodevelopmental delay as a confounding factor from the analysis, associated malformations of a subset of DDD participants with hypospadias and co-existing neurodevelopmental delay were compared to those with a genital abnormality other than hypospadias but again with co-existing neurodevelopmental delay. This analysis showed that cardiovascular and structural brain abnormalities occurred at a significantly higher rate in individuals with hypospadias compared to the ‘no hypospadias’ group. In addition, in a number of patients, these features occurred as a constellation. Both studies mentioned above showed that cardiovascular abnormalities are more likely to occur together with hypospadias, and in order to remove ascertainment bias, DDD participants with associated neurodevelopmental delay were considered for the next step of the investigations which was VCF file re-analysis of DDD patients with hypospadias, neurodevelopmental delay and cardiovascular abnormalities. VCF files of 22 trio and 11 singleton cases were available for re-analysis. A bioinformatic analysis pipeline was created and applied to perform variant filtering and analysis of the trio cases and likely causative variants in four genes (MID1, ADNP, CTNND1 and TRIO), already linked to developmental disorders have been identified. This is the first report to describe hypospadias as an associated clinical feature in relation to the TRIO, CTNND1 and ADNP genes. Additionally, a new multiple malformation syndrome caused by a likely pathogenic variant in the PKN2 gene is delineated. Three (CTNND1, TRIO, and PKN2) of the five genes identified in the family trios are directly interacting with or regulate the function of Rho GTPases. Singleton analysis using a modified bioinformatics pipeline detected a causative alteration in an epigenetic regulator gene (HIST1H1E).
In summary, the application of whole-exome sequencing was deemed a powerful tool in establishing molecular diagnoses for patients with hypospadias and in the discovery of new gene associations. Additional research into the role of Rho GTPases in the development of hypospadias might facilitate our understanding of the mechanisms driving genital development.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: DSD, WES, hypospadias, TRIO, CTNND1, PKN2, HIST1H1E, MID1, ADNP/
Subjects: R Medicine > R Medicine (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Funder's Name: Glasgow Children`s Hospital Charity (GCHC)
Supervisor's Name: Tobias, Professor Edward
Date of Award: 2021
Embargo Date: 13 November 2026
Depositing User: Dr Gabriella Gazdagh
Unique ID: glathesis:2021-82024
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 22 Feb 2021 07:58
Last Modified: 22 Feb 2021 07:58
Thesis DOI: 10.5525/gla.thesis.82024
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