Daniela Burguez1, Márcia Polese-Bonatto2, Laís Alves Jacinto Scudeiro3, Ingemar Björkhem4, Ludger Schöls5, Laura Bannach Jardim6, Ursula Matte7, Maria Luiza Saraiva-Pereira8, Marina Siebert9, Jonas Alex Morales Saute10. 1. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Genetics Identification Laboratory (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. 2. Genetics Identification Laboratory (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 3. Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 4. Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden. 5. Center for Neurology, Hertie Institute for Clinical Brain Research, Eberhard-Karls-University, Tübingen, Germany. 6. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Genetics Identification Laboratory (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 7. Unit of Molecular and Protein Analysis (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Genetics, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 8. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Genetics Identification Laboratory (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Postgraduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 9. Unit of Molecular and Protein Analysis (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Gastroenterology and Hepatology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 10. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Neurology Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Genetics Identification Laboratory (Experimental Research Center), Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil; Postgraduate Program in Medicine: Medical Sciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. Electronic address: jsaute@hcpa.edu.br.
Abstract
BACKGROUND: Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. METHODS: A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. RESULTS: Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11 patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. CONCLUSION: A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil.
BACKGROUND: Molecular diagnosis of hereditary spastic paraplegias (HSP) is a difficult task due to great clinical and genetic heterogeneity. We aimed to characterize clinical and molecular findings of HSP families from Rio Grande do Sul, Brazil; and to evaluate the diagnostic yield of a next-generation sequencing (NGS) panel with twelve HSP-related genes. METHODS: A consecutive series of HSP index cases with familial recurrence of spasticity, consanguinity or thin corpus callosum (TCC) were included in this cross-sectional study. RESULTS: Among the 29 index cases, 51.7% (15/29) received at least a likely molecular diagnosis, and 48.3% (14/29) a defined diagnosis. NGS panel diagnostic yield was 60% for autosomal dominant HSP (6/10, all SPG4), 47.4% for autosomal recessive HSP (9/19: 5 SPG11, 2 SPG7, 1 SPG5 and 1 cerebrotendinous xanthomatosis), and 50% for patients with TCC (3/6, all SPG11). Remarkably, 2/6 SPG11patients presented keratoconus, and tendon xanthomas were absent in the patient with cerebrotendinous xanthomatosis. CONCLUSION: A likely molecular diagnosis was obtained for more than half of families with the NGS panel, indicating that this approach could be employed as a first-line investigation for HSP. SPG4 is the most frequent form of autosomal dominant and SPG11 of autosomal recessive HSP in Southern Brazil.
Authors: Hélio A G Teive; Carlos Henrique F Camargo; Eduardo R Pereira; Léo Coutinho; Renato P Munhoz Journal: Neurogenetics Date: 2022-04-09 Impact factor: 3.017