INIGEM   23989
INSTITUTO DE INMUNOLOGIA, GENETICA Y METABOLISMO
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
DMD GENE SMALL MUTATION SCREENING BYWHOLE EXOME SEQUENCING
Autor/es:
PARMA DIANA; PENAS ALBERTO; GILIBERTO FLORENCIA; LUCE LEONELA; SZIJAN IRENE
Lugar:
Mar del PLata
Reunión:
Congreso; LXI REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC) LXIV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INMUNOLOGÍA (SAI) XLVIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE FARMACOLOGÍA EXPERIMENTAL (SAFE); 2016
Institución organizadora:
SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC)
Resumen:
Duchenne Muscular Dystrophy (DMD) and Becker MuscularDystrophy (BMD) are X-linked genetic diseases caused by mutationsin the DMD gene. DMD is a severe dystrophy that affects1:3500 born males, whereas BMD is less severe and affects1:18000. Molecular alterations responsible for DMD/DMB are grossdeletions and duplications in 70% of cases and small mutationsin the remaining 30%. While large rearrangements are identifiedby MLPA, point mutations are detected by gene sequencing. Thisstudy aimed to detect small mutations in the DMD gene by WholeExome Sequencing (WES) in 9 boys with presumptive clinicaldiagnosis of DMD/DMB and a woman obligate carrier. WES wasperformed by Macrogen service and the pathogenicity of the identifiedvariants was determined according to: its presence in a DMDmutation database; its absence in results of sequence consortiumssuch as 1000genomes and Hapmap; and online predictive softwares(polyphen, SIFT and Mutationtaster). We have found in theaffected boys a range between 7-18 sequence variants in the DMDgene, when in the only woman studied we detected 33. We wereable to identify the disease causing mutations with 100% certaintyin 9 cases which consisted in 5 nonsense mutations, 1 frameshiftdeletion, 2 frameshift duplications and 1 altering a donor consensussplicing site. In 2 of these cases, we also found a missensemutation predicted to have a negative impact on the dystrophinprotein. In the remaining case, we have identified an in-framedeletion determined as a Variant of Uncertain Significance (VUS).Finally, we can conclude that this screening methodology was ableto detect small mutations in the DMD gene in 9/10 individuals, allowingconfirmation of the diagnosis in the boys. Further studiesshould be performed in order to establish the pathogenicity of theVUS. The importance of this work relies on the fact that is the firstone applying WES for DMD/DMB molecular diagnosis in Argentina.