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Ann Hum Genet. 2019 Aug 16. doi: 10.1111/ahg.12345. [Epub ahead of print]

Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years.

Author information

1
Neurology Department, Hospital J.M. Ramos Mejía, CABA, Centro Universitario de Neurología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
2
Neurogenetic Section, Neurology Department, Hospital J.M. Ramos Mejía, CABA, Centro Universitario de Neurología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
3
Movements Disorders Section, Neurology Department, Hospital J.M. Ramos Mejía, CABA, Centro Universitario de Neurología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
4
Neuroophthalmology Section, Neurology Department, Hospital J.M. Ramos Mejía, CABA, Centro Universitario de Neurología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina.
5
Child Neurology Department, Hospital Universitario Austral, Buenos Aires, Argentina.
6
Metabolism Department, Hospital de Niños "Sor María Ludovica" de La Plata, Buenos Aires, Argentina.
7
Instituto de Investigaciones en Medicina Traslacional-CONICET y Facultad de Ciencias Biomédicas-Universidad Austral, Buenos Aires, Argentina.

Abstract

INTRODUCTION AND OBJECTIVES:

Leukodystrophies and genetic leukoencephalopathies constitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques.

MATERIALS AND METHODS:

A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones.

RESULTS:

Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease.

CONCLUSIONS:

Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase.

KEYWORDS:

diagnostic procedure; genetic leukoencephalopathies; leukodystrophies; next-generation sequencing

PMID:
31418856
DOI:
10.1111/ahg.12345

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