RESUMEN
INTRODUCTION/AIMS: Advanced genetic testing including next-generation sequencing (AGT/NGS) has facilitated DNA testing in the clinical setting and greatly expanded new gene discovery for the Charcot-Marie-Tooth neuropathies and other hereditary neuropathies (CMT/HN). Herein, we report AGT/NGS results, clinical findings, and diagnostic yield in a cohort of CMT/HN patients evaluated at our neuropathy care center. METHODS: We reviewed the medical records of all patients with suspected CMT/HN who underwent AGT/NGS at the Hospital for Special Care from January 2017 through January 2020. Patients with variants reported as pathogenic or likely pathogenic were included for further clinical review. RESULTS: We ordered AGT/NGS on 108 patients with suspected CMT/HN. Of these, pathogenic or likely pathogenic variants were identified in 17 patients (diagnostic yield, 15.7%), including 6 (35%) with PMP22 duplications; 3 (18%) with MPZ variants; 2 (12%) with MFN2 variants; and 1 each with NEFL, IGHMBP2, GJB1, BSCL2, DNM2, and TTR variants. Diagnostic yield increased to 31.0% for patients with a positive family history. DISCUSSION: AGT/NGS panels can provide specific genetic diagnoses for a subset of patients with CMT/HN disorders, which improves disease and genetic counseling and prepares patients for disease-focused therapies. Despite these advancements, many patients with known or suspected CMT/HN disorders remain without a specific genetic diagnosis. Continued advancements in genetic testing, such as multiomic technology and better understanding of genotype-phenotype correlation, will further improve detection rates for patients with suspected CMT/HN disorders.
Asunto(s)
Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Pruebas Genéticas/métodos , Variación Genética/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Neuropatía Hereditaria Motora y Sensorial/diagnóstico , Neuropatía Hereditaria Motora y Sensorial/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Triplet 2-(dicyclopropylmethylidene)cyclopentane-1,3-diyl, CP2TMM, has a Deltam(s) = 2 ESR transition revealing hyperfine splitting consistent with coupling to two equivalent alpha hydrogens and five equivalent beta hydrogens and one other hydrogen with a small hyperfine coupling constant. This is consistent only with a conformation in which one cyclopropane ring conjugates with the pi triplet so that the other cyclopropane is twisted allowing the tertiary cyclopropyl hydrogen to hyperconjugate. Geometry optimization of the triplet state of CP2TMM was carried out using the 3-21G basis set with a UHF wave function and while the singlet state was optimized using a GVB perfect pairing wave function. The most stable conformation of each spin state is a C(2)-symmetric structure providing a 10 kcal/mol singlet-triplet energy gap favoring the triplet. This gap is reproduced at the 6-31G level using the 3-21G geometries. However, this structure cannot reproduce the hyperfine splitting observed; 1 kcal/mol higher in energy is an asymmetrical conformation of triplet CP2TMM which can account for the hyperfine interactions.
