The MTSS2 gene codes a protein that plays a role in plasma membrane motion and central nervous system (CNS) development. Mice studies showed that this gene is involved in neurogenesis. In 2022, a de novo mutation, c.2011C>T (p.Arg671Trp), was linked to a developmental disorder, inherited in an autosomal dominant manner. This study presents four new patients with the MTSS2 variant, reinforcing its association with CNS disorders and suggesting it may be a neurological multisystem disease.
Exome Sequencing and Variant Analysis in MTSS2 Cases
Clinical exome sequencing (CES) was performed, with data analyzed using the Geneyx Analysis platform, prioritizing variants based on Human Phenotype Ontology (HPO). Variants were assessed against public databases and evaluated for pathogenicity using multiple predictive tools. All patients exhibited developmental delay, intellectual disability, and microcephaly, along with additional findings such as hypotonia, epilepsy, and dysmorphic facial features, among others.
FIGURE 1
(A) EEG (Pt1) shows poor background activity with generalized 3Hz spike-and-wave discharges, linked to absence seizures and eyelid myoclonus.
(B) Brain MR (Pt1) reveals non-specific anomalies, mainly cerebellar hypoplasia affecting the vermis.
(C) Pt1 images display facial features (short sloping forehead, arched eyebrows with synophrys, high nasal root, short philtrum, dental anomalies), along with back hypertrichosis and scoliosis.
CES identified the heterozygous MTSS2 variant c.2011C>T (p.Arg671Trp) in all patients. For 3 patients where trio analysis was feasible, this variant is determined to be de novo. The variant is absent in population databases (such as gnomAD) and affects a highly conserved residue. Multiple in silico prediction tools suggest a deleterious effect on MTSS2 protein function. ClinVar and LOVD classify it as pathogenic or likely pathogenic. Based on ACMG criteria, this variant is confirmed as pathogenic.
In summary, this study expands the clinical spectrum of MTSS2-related neurodevelopmental disorders by analyzing four new patients with the recurrent c.2011C>T (p.Arg671Trp) variant. All patients exhibited developmental delay, intellectual disability, and microcephaly, with additional features including ocular anomalies, skeletal abnormalities, and hearing loss. These results suggest a primarily neurological but multisystem disorder. Further research is needed to refine genotype-phenotype correlations and assess potential extra-neurological manifestations.
Abbreviations Glossary:
- MTSS2 (Metastasis Suppressor 2) – A gene involved in plasma membrane dynamics and CNS development.
- CNS (Central Nervous System) – The brain and spinal cord, responsible for processing and transmitting neural signals.
- CES (Clinical Exome Sequencing) – A genetic test analyzing the coding regions of genes to identify disease-causing variants.
- HPO (Human Phenotype Ontology) – A standardized vocabulary describing human phenotypic abnormalities.
- EEG (Electroencephalogram) – A test measuring electrical activity in the brain, used to detect neurological conditions.
- MR (Magnetic Resonance Imaging, MRI) – A medical imaging technique that provides detailed brain and body scans.
- gnomAD (Genome Aggregation Database) – A database compiling human genetic variation from diverse populations.
- ACMG (American College of Medical Genetics and Genomics) – An organization providing guidelines for genetic variant classification.
- ClinVar – A public database that aggregates information on genetic variants and their clinical significance.
- LOVD (Leiden Open Variation Database) – A database for sharing genetic variant information.
