@article {17, title = {The sensitivity of exome sequencing in identifying pathogenic mutations for LGMD in the United States.}, journal = {J Hum Genet}, volume = {62}, year = {2017}, month = {2017 Feb}, pages = {243-252}, abstract = {

The current study characterizes a cohort of limb-girdle muscular dystrophy (LGMD) in the United States using whole-exome sequencing. Fifty-five families affected by LGMD were recruited using an institutionally approved protocol. Exome sequencing was performed on probands and selected parental samples. Pathogenic mutations and cosegregation patterns were confirmed by Sanger sequencing. Twenty-two families (40\%) had novel and previously reported pathogenic mutations, primarily in LGMD genes, and also in genes for Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, congenital myopathy, myofibrillar myopathy, inclusion body myopathy and Pompe disease. One family was diagnosed via clinical testing. Dominant mutations were identified in COL6A1, COL6A3, FLNC, LMNA, RYR1, SMCHD1 and VCP, recessive mutations in ANO5, CAPN3, GAA, LAMA2, SGCA and SGCG, and X-linked mutations in DMD. A previously reported variant in DMD was confirmed to be benign. Exome sequencing is a powerful diagnostic tool for LGMD. Despite careful phenotypic screening, pathogenic mutations were found in other muscle disease genes, largely accounting for the increased sensitivity of exome sequencing. Our experience suggests that broad sequencing panels are useful for these analyses because of the phenotypic overlap of many neuromuscular conditions. The confirmation of a benign DMD variant illustrates the potential of exome sequencing to help determine pathogenicity.

}, keywords = {Base Sequence, Distal Myopathies, Exome, Female, Genetic Testing, Glycogen Storage Disease Type II, Humans, Male, Muscular Dystrophies, Limb-Girdle, Muscular Dystrophy, Duchenne, Muscular Dystrophy, Facioscapulohumeral, Mutation, Myopathies, Structural, Congenital, Sequence Analysis, DNA, United States}, issn = {1435-232X}, doi = {10.1038/jhg.2016.116}, author = {Reddy, Hemakumar M and Cho, Kyung-Ah and Lek, Monkol and Estrella, Elicia and Valkanas, Elise and Jones, Michael D and Mitsuhashi, Satomi and Darras, Basil T and Amato, Anthony A and Lidov, Hart Gw and Brownstein, Catherine A and Margulies, David M and Yu, Timothy W and Salih, Mustafa A and Kunkel, Louis M and MacArthur, Daniel G and Kang, Peter B} } @article {51, title = {Loss-of-Function Mutations in FRRS1L Lead to an Epileptic-Dyskinetic Encephalopathy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 06 02}, pages = {1249-1255}, abstract = {

Glutamatergic neurotransmission governs excitatory signaling in the mammalian brain, and abnormalities of glutamate signaling have been shown to contribute to both epilepsy and hyperkinetic movement disorders. The etiology of many severe childhood movement disorders and epilepsies remains uncharacterized. We describe a neurological disorder with epilepsy and prominent choreoathetosis caused by biallelic pathogenic variants in FRRS1L, which encodes an AMPA receptor outer-core protein. Loss of FRRS1L function attenuates AMPA-mediated currents, implicating chronic abnormalities of glutamatergic neurotransmission in this monogenic neurological disease of childhood.

}, keywords = {alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid, Brain Diseases, Electrophysiology, Epilepsy, Female, Humans, Hyperkinesis, Infant, Male, Membrane Proteins, Mutation, Nerve Tissue Proteins, Pedigree, Synaptic Transmission}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.04.008}, author = {Madeo, Marianna and Stewart, Michelle and Sun, Yuyang and Sahir, Nadia and Wiethoff, Sarah and Chandrasekar, Indra and Yarrow, Anna and Rosenfeld, Jill A and Yang, Yaping and Cordeiro, Dawn and McCormick, Elizabeth M and Muraresku, Colleen C and Jepperson, Tyler N and McBeth, Lauren J and Seidahmed, Mohammed Zain and El Khashab, Heba Y and Hamad, Muddathir and Azzedine, Hamid and Clark, Karl and Corrochano, Silvia and Wells, Sara and Elting, Mariet W and Weiss, Marjan M and Burn, Sabrina and Myers, Angela and Landsverk, Megan and Crotwell, Patricia L and Waisfisz, Quinten and Wolf, Nicole I and Nolan, Patrick M and Padilla-Lopez, Sergio and Houlden, Henry and Lifton, Richard and Mane, Shrikant and Singh, Brij B and Falk, Marni J and Mercimek-Mahmutoglu, Saadet and Bilguvar, Kaya and Salih, Mustafa A and Acevedo-Arozena, Abraham and Kruer, Michael C} } @article {141, title = {Mutation in GM2A Leads to a Progressive Chorea-dementia Syndrome.}, journal = {Tremor Other Hyperkinet Mov (N Y)}, volume = {5}, year = {2015}, month = {2015}, pages = {306}, abstract = {

BACKGROUND: The etiology of many cases of childhood-onset chorea remains undetermined, although advances in genomics are revealing both new disease-associated genes and variant phenotypes associated with known genes.

METHODS: We report a Saudi family with a neurodegenerative course dominated by progressive chorea and dementia in whom we performed homozygosity mapping and whole exome sequencing.

RESULTS: We identified a homozygous missense mutation in GM2A within a prominent block of homozygosity. This mutation is predicted to impair protein function.

DISCUSSION: Although discovered more than two decades ago, to date, only five patients with this rare form of GM2 gangliosidosis have been reported. The phenotype of previously described GM2A patients has been typified by onset in infancy, profound hypotonia and impaired volitional movement, intractable seizures, hyperacusis, and a macular cherry red spot. Our findings expand the phenotypic spectrum of GM2A mutation-positive gangliosidosis to include generalized chorea without macular findings or hyperacusis and highlight how mutations in neurodegenerative disease genes may present in unexpected ways.

}, issn = {2160-8288}, doi = {10.7916/D8D21WQ0}, author = {Salih, Mustafa A and Seidahmed, Mohammed Z and El Khashab, Heba Y and Hamad, Muddathir H A and Bosley, Thomas M and Burn, Sabrina and Myers, Angela and Landsverk, Megan L and Crotwell, Patricia L and Bilguvar, Kaya and Mane, Shrikant and Kruer, Michael C} }