Targeted NGS identifies pathogenic variants in 81% of a large Indian RASopathy cohort, detailing gene spectrum.
Background
RASopathies are a group of developmental disorders affecting 1 in 1000 individuals, driven by dysregulation of the RAS/mitogen-activated protein kinase (MAPK) pathway. These conditions, including Noonan Syndrome, Cardio-facio-cutaneous syndrome, and Costello syndrome, present with overlapping clinical features, making accurate diagnosis challenging through clinical assessment alone. Current diagnostic approaches often fall short in providing a definitive molecular diagnosis, which is crucial for genetic counseling, prognosis, and potential future targeted therapies. This study addresses the diagnostic gap by employing advanced molecular tools.
Study Design
Researchers performed targeted sequencing on 130 samples from individuals clinically diagnosed with RASopathies within a large Indian cohort. A multigene panel comprising 21 RASopathy genes was utilized for molecular analysis. The primary objective was to identify and characterize genetic variations, including pathogenic, likely pathogenic, and variants of uncertain significance (VUS). The study aimed to establish the molecular profile of this specific population and assess the effectiveness of targeted gene panels as a diagnostic tool, without a specific intervention or control arm beyond standard diagnostic practice.
Results
Molecular analysis successfully identified genetic variations in 74 individuals (57%) out of the 130 samples. Of these, 60/74 cases (81%) harbored pathogenic or likely pathogenic variations, significantly improving diagnostic clarity. Additionally, 13 individuals (17.5%) presented with variant(s) of uncertain significance (VUS), and one novel variant was identified in RASA2, though its pathogenicity remains unestablished. Specific gene variations were detailed for common RASopathies:
In individuals with Noonan Syndrome, pathogenic variants were identified across eight different genes, primarily
PTPN11,SOS1,RAF1, andLZTR1. For Cardio-facio-cutaneous syndrome, nine clinically diagnosed cases harbored variations inBRAF,MAP2K2, andMAP2K1. All nine individuals diagnosed with Costello syndrome exhibited the specificc.34G>Avariant inHRAS. This comprehensive molecular profiling highlights the diverse genetic landscape within this cohort.
Key Findings
- Genetic variations were detected in 57% (74/130) of individuals with RASopathies.
- Pathogenic or likely pathogenic variants were found in 81% (60/74) of cases with identified variations.
- Noonan Syndrome cases showed pathogenic variants in
PTPN11,SOS1,RAF1, andLZTR1. - Cardio-facio-cutaneous syndrome cases harbored variations in
BRAF,MAP2K2, andMAP2K1. - All nine Costello syndrome cases shared the
c.34G>Avariant inHRAS.
Why It Matters
This study significantly advances the understanding of RASopathy genetics in the Indian population, providing a crucial molecular and clinical profile. Improved diagnostic yield via targeted gene panels means more individuals can receive a definitive molecular diagnosis, which is vital for accurate genetic counseling, family planning, and personalized management strategies. While this study focuses on diagnosis, a precise genetic understanding is foundational for future therapeutic interventions, such as those targeting the MAPK pathway (e.g., MEK inhibitors like trametinib, as hinted by domain context). This approach could become a standard protocol for diagnosing RASopathies in diverse populations, moving beyond solely clinical assessments to precision medicine.
rasopathies
genetic-disorders
next-generation-sequencing
noonan-syndrome
costello-syndrome
cardio-facio-cutaneous-syndrome