Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Ana TöpfVolker Straub

Abstract

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. 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. We identified suspected pathogenic variants in 52% of patients across 87 genes. We detected 401 novel variants, 116 of which were recurrent. Variants in CAPN3, DYSF, ANO5, DMD, RYR1, TTN, COL6A2, and SGCA collectively accounted for over half of the solved cases; while variants in newer disease genes, such as BVES and POGLUT1, were also found. The remaining well-characterized unsolved patients (48%) need further investigation. 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 dis...Continue Reading

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Citations

Jun 20, 2020·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·F FatehiS Nafissi
Oct 14, 2020·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·B KrettJ Vissing
Jan 3, 2021·Journal of Neuromuscular Diseases·L Ten DamAnneke J van der Kooi
Apr 17, 2021·American Journal of Human Genetics·Sandra CoppensPeter B Kang
May 1, 2021·International Journal of Molecular Sciences·Dèlia YuberoFrancesc Palau
May 6, 2021·Movement Disorders : Official Journal of the Movement Disorder Society·Michael ZechKonrad Oexle
May 7, 2021·Frontiers in Endocrinology·Carolina CecchettiAlessandra Gambineri
Jun 11, 2021·The Protein Journal·Dimitra G GeorganopoulouChih-Kao Hu
Jul 4, 2021·Neuromuscular Disorders : NMD·Sacha E GandhiMaria Elena Farrugia
Jul 3, 2021·Neuromuscular Disorders : NMD·Jorge Alonso-PérezJordi Díaz-Manera
Oct 9, 2021·Der Nervenarzt·Andrea GangfußAndreas Roos
Jan 16, 2022·American Journal of Human Genetics·Andrew G SharoSteven E Brenner

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Methods Mentioned

BETA
exome sequencing
biopsies
RNA-Seq

Software Mentioned

NMD
ClinVar
Ensembl Variant Effect Predictor
SEQ
TREAT
MYO
PhenoTips

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