The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome

Abstract

High-throughput sequencing has become a standard first-tier approach for both diagnostics and research-based genetic testing. Consequently, this hypothesis-free testing manner has revealed the true breadth of clinical features for many established genetic disorders, including Meier-Gorlin syndrome (MGORS). Previously known as ear-patella short stature syndrome, MGORS is characterized by growth delay, microtia, and patella hypo/aplasia, as well as genital abnormalities, and breast agenesis in females. Following the initial identification of genetic causes in 2011, a total of 13 genes have been identified to date associated with MGORS. In this review, we summarise the genetic and clinical findings of each gene associated with MGORS and highlight molecular insights that have been made through studying patient variants. We note interesting observations arising across this group of genes as the number of patients has increased, such as the unusually high number of synonymous variants affecting splicing in CDC45 and a subgroup of genes that also cause craniosynostosis. We focus on the complicated molecular genetics for DONSON, where we examine potential genotype-phenotype patterns using the first 3D structural model of DONSON. The canonical role of all proteins associated with MGORS are involved in different stages of DNA replication and in addition to summarising how patient variants impact on this process, we discuss the potential contribution of non-canonical roles of these proteins to the pathophysiology of MGORS.

DONSON is required for CMG helicase assembly in the mammalian cell cycle

“…The importance of DONSON for CMG helicase assembly in mammalian cells provides a mechanistic explanation for why hypomorphic mutations in human DONSON lead to Meier‐Gorlin syndrome, consistent with the fact that the other 12 Meier‐Gorlin genes encode components of the CMG helicase or factors that mediate or regulate helicase assembly (Nielsen‐Dandoroff et al , 2023 ). Primordial Microcephalic Dwarfism syndromes such as Meier‐Gorlin result from defects in cell proliferation during embryogenesis, to which brain development is particularly sensitive (Klingseisen & Jackson, 2011 ).…”

“…The CMG helicase is essential for cell viability, but partial loss of function or defects in helicase assembly cause a form of microcephalic primordial dwarfism in humans called Meier‐Gorlin syndrome, which is associated with hypomorphic mutations in 13 genes (Klingseisen & Jackson, 2011 ; Bellelli & Boulton, 2021 ; Nielsen‐Dandoroff et al , 2023 ). Of these, 12 encode helicase subunits or factors with a well characterised role in CMG helicase assembly (three subunits of ORC, the CDC6 protein, CDT1 and its regulator Geminin, CDC45, three subunits of MCM2‐7 and two components of GINS).…”

Reconstitution of human DNA licensing and the structural and functional analysis of key intermediates

“…To date, a number of cancer-associated mutations, as well as several mutations linked to the Meier-Gorlin syndrome, a rare human disease associated with primordial dwarfism 51 , have been mapped to DNA licensing factors. Still, their functional relevance has yet to be discovered due to a lack of structural information and an efficient in vitro assay to test the impact of the mutations [52][53][54] .…”

A second hotspot for pathogenic exon-skipping variants in CDC45

“…Meier-Gorlin syndrome (MGORS) is characterised by reduced growth, microtia and patella hypo/aplasia and is a disorder associated with components involved in the organisation and initiation of DNA replication [ 6 ]. Biallelic variants in CDC45 are associated with a distinct spectrum of clinical features designated as MGORS7 (MIM 617063) [ 6 – 10 ]; while craniosynostosis is almost always present, many patients also have microtia and patella hypo/aplasia, more typical of MGORS.…”

“…Meier-Gorlin syndrome (MGORS) is characterised by reduced growth, microtia and patella hypo/aplasia and is a disorder associated with components involved in the organisation and initiation of DNA replication [ 6 ]. Biallelic variants in CDC45 are associated with a distinct spectrum of clinical features designated as MGORS7 (MIM 617063) [ 6 – 10 ]; while craniosynostosis is almost always present, many patients also have microtia and patella hypo/aplasia, more typical of MGORS. There does not appear to be a straightforward relationship between variant type and severity of presentation; this is exemplified by a sib-pair identified in the initial CDC45 -cohort where one sibling has typical MGORS features in the absence of craniosynostosis, whereas the younger sibling has a clear craniosynostosis phenotype [ 7 ].…”