Antenatal Presentation of MRPS22-Related Mitochondrial Disease Confirmed With Rapid Proteomics
Liana N Semcesen1, Megan Ball2,3,4, Daniella H Hock1,2,5
1Department of Biochemistry and Pharmacology Bio21 Molecular Science and Biotechnology Institute, University of Melbourne Parkville Victoria Australia.
Abstract:
MRPS22-related mitochondrial disease (MIM#611719) is a rare autosomal recessive disorder caused by defects in the mitochondrial ribosomal protein S22, a component of the small mitoribosomal subunit essential for mitochondrial translation. Of the few reported cases, most present antenatally with a severe phenotype, conveying a poor prognosis. We describe a fetus with severe antenatal-onset MRPS22-related mitochondrial disease and the use of multi-omics in the molecular diagnosis. A primigravida underwent termination of pregnancy following identification of multiple congenital anomalies (hydrops fetalis, microcephaly, corpus callosal agenesis, periventricular cysts and cardiac hypertrophy) on ultrasound at 20 + 2 weeks' gestation, confirmed on fetal magnetic resonance imaging. Trio genome sequencing revealed compound heterozygous variants in MRPS22 (NM_020191.4: c.509G>A; p.(Arg170His) and c.565C>G; p.(Arg189Gly)). Rapid proteomic analysis demonstrated destabilisation of the small mitoribosomal subunit and combined reduction of OXPHOS complexes, supporting the pathogenicity of the variants. This case consolidates the antenatal phenotype of severe MRPS22-related disease and highlights the importance of considering mitochondrial disease in the differential diagnosis of congenital anomalies, especially hydrops fetalis and corpus callosum anomalies. This study provides evidence for the utility of multi-omic approaches (trio genome sequencing, proteomics) in confirming variant pathogenicity following pregnancy loss, enabling accurate diagnosis, and informing reproductive counselling for affected families.
Insights
Severe MRPS22 mitochondrial disease, a rare genetic disorder, can present antenatally with multiple congenital anomalies. Multi-omics approaches aid in diagnosing this condition and informing family reproductive choices.
Area of Science:
- Genetics
- Molecular Biology
- Mitochondrial Biology
Background:
- MRPS22-related mitochondrial disease is a rare, severe autosomal recessive disorder.
- It stems from defects in mitochondrial ribosomal protein S22, crucial for mitochondrial translation.
- Most reported cases exhibit antenatal onset and a poor prognosis.
Purpose of the Study:
- To describe a fetus with severe antenatal MRPS22-related mitochondrial disease.
- To demonstrate the utility of multi-omics in molecular diagnosis.
- To highlight the importance of considering mitochondrial disease in congenital anomaly diagnoses.
Main Methods:
- Fetal ultrasound and MRI for anomaly detection.
- Trio whole-genome sequencing for genetic variant identification.
- Proteomic analysis to assess mitoribosomal subunit stability and OXPHOS complex levels.
Main Results:
- Identified compound heterozygous variants in MRPS22 (c.509G>A and c.565C>G).
- Proteomics confirmed small mitoribosomal subunit destabilization and reduced OXPHOS complexes.
- The findings support the pathogenicity of the identified MRPS22 variants.
Conclusions:
- This case reinforces the severe antenatal phenotype of MRPS22-related mitochondrial disease.
- Multi-omic approaches are valuable for confirming variant pathogenicity after pregnancy loss.
- Early consideration of mitochondrial disease is vital for diagnosing congenital anomalies and reproductive counseling.
