RASオパチー患者の分子および臨床プロファイル：標的次世代シーケンシングパネルの結果と14の新規疾患原因バリアントの同定

RASopathies are among the most prevalent genetic syndromes caused by variants in the Ras/MAPK signaling pathway, affecting various systems such as the heart, craniofacial features, skin, musculoskeletal system, hearing, and vision. They can also increase the risk of secondary malignancies. Despite clinical overlaps, distinguishing features are crucial for diagnosis, as different variants lead to distinct clinical implications. This study reviews the molecular and clinical characteristics of RASopathies, focusing on neurofibromatosis type 1 (NF1) and non-NF1 RASopathies.

The study analyzed 76 patients referred to our outpatient clinic over a 6-year period, all of whom were clinically diagnosed with RASopathy and confirmed in most cases by molecular testing. Patient files, clinical photographs, and laboratory results were reviewed and analyzed. A targeted multigene next-generation sequencing panel test was performed, followed by Sanger sequencing for both confirmation and segregation analysis. Multiplex ligation-dependent probe amplification was conducted in a patient with normal sequence results but strong clinical suspicion, to identify potential deletions.

We identified 44 pathogenic, 25 likely pathogenic variants, and 6 variants of uncertain significance based on American College of Medical Genetics and Genomics (ACMG) criteria. Among these, 14 novel variants were found - 13 in the NF1 gene and one in SOS1. NF1 variants were present in 51 cases. Additional variants, likely to represent clinically significant findings, were identified in PTPN11 (n = 11), RAF1 (n = 4), SOS1 (n = 3), RIT1 (n = 3), KRAS (n = 1), NRAS (n = 1), SOS2 (n = 1), and BRAF (n = 1). Diagnoses included 49 patients with NF1, 21 with Noonan syndrome, 2 with neurofibromatosis-Noonan syndrome, 2 with Noonan syndrome with multiple lentigines, and 1 with cardiofaciocutaneous syndrome. Here, 12% of NF1 variants were located in exon 21, 36% of PTPN11 variants in exon 3, and 75% of RAF1 variants in exon 7.

RASopathies have a broad molecular and clinical spectrum, complicating diagnosis and management. Accurate clinical correlation and molecular analysis are essential, as different RASopathy syndromes can result from variants in the same genes, while the same syndrome may arise from different genetic alterations. This study identifies novel variants and emphasizes the need for precise diagnostic approaches in these complex disorders.