Congratulations to Professor Sally Ann Lynch who has had three papers recently published

Congratulations to UCD School of Medicine’s Professor Sally Ann Lynch who has recently had three papers published.

Two papers were published in The American Journal of Human Genetics:

Heterozygous pathogenic variants in the splicing factor SF1 lead to a large spectrum of neurodevelopmental disorders (Prof Sally Ann Lynch was co-author on this paper)

Summary

Alternative splicing is highly prevalent in the brain where it orchestrates key processes such as neurogenesis and synaptogenesis, both essential for the nervous system’s complexity and plasticity. Dysregulation of splicing has increasingly been linked to neurodevelopmental disorders. Here, we describe unrelated individuals carrying de novo, likely deleterious heterozygous variants in Splicing Factor 1 (SF1), all presenting with neurodevelopmental disorders of variable severity, frequently accompanied by autistic traits and other non-specific features. SF1 is a core component of pre-mRNA processing, facilitating early spliceosome assembly at the 3′ splice site and regulating alternative splicing. We conducted functional studies in neural progenitor cells, which showed that SF1 downregulation alters gene expression and alternative splicing programs, particularly in genes involved in neuronal differentiation, synaptic transmission, and axonal guidance, processes fundamental to brain development. Together, these findings establish SF1 dysfunction as an additional spliceosomopathy contributing to neurodevelopmental disorders and underscore its essential role in human neurodevelopment and disease.

The paper can be accessed online (opens in a new window)here.

An OGT Missense Variant With Impaired Enzyme Activity in a Child With Severe Developmental Delay and Hepatoblastoma

Abstract

O-GlcNAc transferase (OGT) and its antagonist O-GlcNAcase (OGA) regulate protein O-GlcNAcylation, a highly conserved post-translational modification involved in metabolic sensing. Pathogenic variants in the OGT gene cause an X-linked congenital disorder of glycosylation (OGT-CDG) presenting developmental delay, hypotonia, intellectual disability, and dysmorphic features. Here, we report on a child with developmental delay, hypotonia, and dysmorphic features who was found to carry a hemizygous novel OGT variant. This child also developed hepatoblastoma by the age of 17 months. OGT-CDG was diagnosed by exome sequencing that identified a de novo missense variant in the OGT gene. Functional validation by Western blot on patient-derived fibroblasts showed reduced O-GlcNAcylation and OGA expression, while significantly reduced enzyme activity in vitro confirmed the pathogenicity of the variant. To date, no patients with OGT-CDGs have been reported with hepatoblastoma or other malignancies. Although the occurrence of hepatoblastoma in the proband might be coincidental, the role of O-GlcNAcylation in cancer suggests that the deficiency of OGT activity might be associated with increased cancer risk.

The paper can be accessed online (opens in a new window)here.

Another paper was published in the British Journal of Haematology:

Germline mosaicism in a family affected by Diamond–Blackfan anaemia

The paper can be accessed online (opens in a new window)here.