@article {911, title = {Sequential targeted exome sequencing of 1001 patients affected by unexplained limb-girdle weakness.}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 09}, pages = {1478-1488}, abstract = {

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 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.

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.

}, keywords = {Anoctamins, Exome, Glucosyltransferases, Humans, Muscular Dystrophies, Limb-Girdle, Whole Exome Sequencing}, issn = {1530-0366}, doi = {10.1038/s41436-020-0840-3}, author = {Topf, Ana and Johnson, Katherine and Bates, Adam and Phillips, Lauren and Chao, Katherine R and England, Eleina M and Laricchia, Kristen M and Mullen, Thomas and Valkanas, Elise and Xu, Liwen and Bertoli, Marta and Blain, Alison and Casas{\'u}s, Ana B and Duff, Jennifer and Mroczek, Magdalena and Specht, Sabine and Lek, Monkol and Ensini, Monica and MacArthur, Daniel G and Straub, Volker} } @article {755, title = {Severe neurodevelopmental disease caused by a homozygous TLK2 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {383-387}, abstract = {

A distinct neurodevelopmental phenotype characterised mainly by mild motor and language delay and facial dysmorphism, caused by heterozygous de novo or dominant variants in the TLK2 gene has recently been described. All cases reported carried either truncating variants located throughout the gene, or missense changes principally located at the C-terminal end of the protein mostly resulting in haploinsufficiency of TLK2. Through whole exome sequencing, we identified a homozygous missense variant in TLK2 in a patient showing more severe symptoms than those previously described, including cerebellar vermis hypoplasia and West syndrome. Both parents are heterozygous for the variant and clinically unaffected highlighting that recessive variants in TLK2 can also be disease causing and may act through a different pathomechanism.

}, keywords = {Adult, Cerebellum, Child, Developmental Disabilities, Female, Heterozygote, Homozygote, Humans, Infant, Male, Mutation, Missense, Nervous System Malformations, Pedigree, Protein Kinases, Spasms, Infantile}, issn = {1476-5438}, doi = {10.1038/s41431-019-0519-x}, author = {Topf, Ana and Oktay, Yavuz and Balaraju, Sunitha and Yilmaz, Elmasnur and Sonmezler, Ece and Yis, Uluc and Laurie, Steven and Thompson, Rachel and Roos, Andreas and MacArthur, Daniel G and Yaramis, Ahmet and G{\"u}ng{\"o}r, Serdal and Lochm{\"u}ller, Hanns and Hiz, Semra and Horvath, Rita} }