Concurrent Invited Session I, 22. Uncovering Missing Heritability in Mendelian Diseases: Lessons from Inherited Eye Diseases, ASHG 2018 meeting, San Diego, October 16-20
October 17, 10:30 AM–12:30 PM
Room 6F, Upper Level, San Diego Convention Center
Moderators: Elfride De Baere, Ghent Univ, Ghent, Belgium and Elena V. Semina, Med Col Wisconsin, Milwaukee
Eye diseases are among the most common inherited human disorders. Around one third of the known genetic defects or syndromes involve the eye. Eye research has often blazed a trail for many disciplines to follow, giving a lead in (functional) genomics, transcriptomics, genome editing, stem cell biology, animal models of disease, and the development of novel therapeutic approaches such as gene therapy. Geneticists have identified a large proportion of the genes underlying genetic eye diseases. However, the coding genetic defects identified only account for part of the morbid genome of inherited eye diseases, suggesting new classes of defects such as non-coding defects or frequent hypomorphic alleles in known or undiscovered eye disease genes. These changes are either largely undetected by conventional genomic strategies or are difficult to interpret. This session brings together a diverse group of experts in gene discovery and mechanisms of disease, bioinformatics, model systems and gene editing. They have been committed to identify genes and functionally characterize genetic defects, both coding and non-coding, that are specifically or predominantly expressed in the eye and therefore play an important role in eye function as well as in the pathogenesis of inherited eye disorders. Together, this session will address knowledge gaps in the pathogenesis of genetic eye diseases through cutting-edge approaches related to bioinformatics, (functional) genomics, genome editing and model systems as a paradigm for precision medicine in Mendelian disease.
New paper out: Biallelic sequence and structural variants in RAX2 are a novel cause for autosomal recessive inherited retinal disease
New paper out: Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development
Check out our latest paper published in Genetics in Medicine. You can read the abstract below, for the full text click here.
Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.
Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.
Results: We identified a homozygous ESR2 variant, c.541_543del p.(Asn181del), located in the highly conserved DNA-binding domain of ER-β, in an individual with syndromic 46,XY DSD. Two additional heterozygous missense variants, c.251G>T p.(Gly84Val) and c.1277T>G p.(Leu426Arg), located in the N-terminus and the ligand-binding domain of ER-β, were found in unrelated, nonsyndromic 46,XY DSD cases. Significantly increased transcriptional activation and an impact on protein conformation were shown for the p.(Asn181del) and p.(Leu426Arg) variants. Testicular ESR2 expression was previously documented and ER-β immunostaining was positive in the developing intestine and eyes.
Conclusion: Our study supports a role for ESR2 as a novel candidate gene for 46,XY DSD.
On Friday December 8 2017 Basamat ALMOALLEM, a Saudi ophthalmologist in training, successfully obtained her PhD in Health Sciences on the basis of her doctoral thesis ‘Unraveling the molecular basis of genetically heterogeneous developmental eye disorders’. Her findings unveiled examples of care valued by both patients and clinicians in the field of ophthalmic genetics. She has taken great steps towards tackling some of the challenges ophthalmic genetics is facing today.
For our new team website we obviously needed a nice team picture. The crime scene of choice was the historic centre of Ghent. We would like to thank our photographer Pieter-Jan Volders for the beautiful photos. In the picture below you can see the models getting ready for the shoot.