Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness
Por:
Topf, A, Johnson, K, Bates, A, Phillips, L, Chao, KR, England, EM, Laricchia, KM, Mullen, T, Valkanas, E, Xu, LW, Bertoli, M, Blain, A, Casasus, AB, Duff, J, Mroczek, M, Specht, S, Lek, M, Ensini, M, MacArthur, DG, Straub, V, Alonso-Pérez J., González-Quereda L.
Publicada:
1 sep 2020
Ahead of Print:
1 jun 2020
Resumen:
Purpose Several hundred genetic muscle diseases have been described, all of which are rare. Their clinical and genetic heterogeneity means that a genetic diagnosis is challenging. We established an international consortium, MYO-SEQ, to aid the work-ups of muscle disease patients and to better understand disease etiology. Methods Exome sequencing was applied to 1001 undiagnosed patients recruited from more than 40 neuromuscular disease referral centers; standardized phenotypic information was collected for each patient. Exomes were examined for variants in 429 genes associated with muscle conditions. Results We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants inCAPN3,DYSF,ANO5,DMD,RYR1,TTN,COL6A2, andSGCAcollectively accounted for over half of the solved cases; while variants in newer disease genes, such asBVESandPOGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. Conclusion Using our unique infrastructure, we developed a pathway to expedite muscle disease diagnoses. Our data suggest that exome sequencing should be used for pathogenic variant detection in patients with suspected genetic muscle diseases, focusing first on the most common disease genes described here, and subsequently in rarer and newly characterized disease genes.
Filiaciones:
Topf, A:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Johnson, K:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Univ, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Bates, A:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Phillips, L:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Chao, KR:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
England, EM:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Laricchia, KM:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Mullen, T:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Valkanas, E:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Xu, LW:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Bertoli, M:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Tyne NHS Fdn Trust, Northern Genet Serv, Newcastle Upon Tyne, Tyne & Wear, England
Blain, A:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Casasus, AB:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Duff, J:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Mroczek, M:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Specht, S:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Lek, M:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA
Ensini, M:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Directorate Gen Res & Innovat, Directorate E, Unit Combatting Dis E2, Brussels, Belgium
MacArthur, DG:
Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA
Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
Garvan Inst Med Res, Ctr Populat Genom, Sydney, NSW, Australia
Murdoch Childrens Res Inst, Ctr Populat Genom, Melbourne, Vic, Australia
Straub, V:
Newcastle Univ, John Walton Muscular Dystrophy Res Ctr, Translat & Clin Res Inst, Newcastle Upon Tyne, Tyne & Wear, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, Tyne & Wear, England
Alonso-Pérez J.:
Neuromuscular Disorders Unit, Neurology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
González-Quereda L.:
Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), Madrid, Spain
Genetics Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
hybrid, Green Published
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