Abstract Pathogenic variants in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for cystic fibrosis (CF), the commonest monogenic autosomal recessive disease, and CFTR-related disorders in infants and youth. Diagnosis of such diseases relies on clinical, functional, and molecular studies. To date, over 2,000 variants have been described on CFTR (~40% missense). Since few of them have confirmed pathogenicity, in silico analysis could help molecular diagnosis and genetic counseling. Here, the pathogenicity of 779 CFTR missense variants was predicted by consensus predictor PredictSNP and compared to annotations on CFTR2 and ClinVar. Sensitivity and specificity analysis was divided into modeling and validation phases using just variants annotated on CFTR2 and/or ClinVar that were not in the validation datasets of the analyzed predictors. After validation phase, MAPP and PhDSNP achieved maximum specificity but low sensitivity. Otherwise, SNAP had maximum sensitivity but null specificity. PredictSNP, PolyPhen-1, PolyPhen-2, SIFT, nsSNPAnalyzer had either low sensitivity or specificity, or both. Results showed that most predictors were not reliable when analyzing CFTR missense variants, ratifying the importance of clinical information when asserting the pathogenicity of CFTR missense variants. Our results should contribute to clarify decision making when classifying the pathogenicity of CFTR missense variants.

Relatamos o caso de uma mulher de 30 anos com quadro de fraqueza muscular nos membros inferiores com predomínio distal com início há 7 anos. Na evolução apresentou fraqueza muscular nos membros superiores. O exame físico mostrava nervos cranianos sem alterações, hipotrofia bilateral de quadriceps e interósseos dos pés, redução da força muscular mais intensa em tibiais anteriores e interósseos dorsais dos pés e reflexos tendinosos globalmente hipoativos. Foi realizado teste de estimulação repetitiva que mostrou decremento maior que 10% no nervo fibular e ulnar. A dosagem de anticorpos anti-receptor de acetilcolina foi positiva. Tomografia computadorizada de tórax foi normal. Dosagem de hormônios tireoidianos mostrou evidências laboratoriais de hipertireoidismo, porém sem manifestações clínicas. Foi iniciado tratamento com piridostigmina havendo melhora importante do quadro clínico. A fraqueza distal é um sintoma inicial raro na miastenia grave (MG). Contudo, a MG deve entrar no diagnóstico diferencial de doenças que cursam com fraqueza muscular distal de membros superiores ou inferiores.

We report the case of a 30-year-old woman with a 7-year history of distal lower limbs weakness that evolved to upper limbs weakness. On neurological examination, she presented normal cranial nerves, bilateral quadriceps and feet interosseous atrophy, normal muscular tonus, muscular weakness more severe in dorsal feet interosseous and anterior tibial, and decreased deep tendon reflexes. Repetitive nerve stimulation of the ulnar and fibular nerves showed a decrement greater than 10% of the compound muscle action potential. Antibody against acetylcholine receptor titer was positive. Computed tomography scan of the thorax was normal. Thyroid function tests showed evidence of hyperthyroidism. Distal muscular weakness is a rare onset presentation of myasthenia gravis. However, myasthenia gravis must be considered in the differential diagnosis of distal limb weakness.