@article {756, title = {Congenital myasthenic syndrome with mild intellectual disability caused by a recurrent SLC25A1 variant.}, journal = {Eur J Hum Genet}, volume = {28}, year = {2020}, month = {2020 03}, pages = {373-377}, abstract = {

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of disorders caused by mutations which lead to impaired neuromuscular transmission. SLC25A1 encodes a mitochondrial citrate carrier, associated mainly with the severe neurometabolic disease combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). We previously reported a single family with a homozygous missense variant in SLC25A1 with a phenotype restricted to relatively mild CMS with intellectual disability, but to date no additional cases of this CMS subtype had been reported. Here, we performed whole exome sequencing (WES) in three additional and unrelated families presenting with CMS and mild intellectual disability to identify the underlying causative gene. The WES analysis revealed the presence of a homozygous c.740G>A; p.(Arg247Gln) missense SLC25A1 variant, the same SLC25A1 variant as identified in the original family with this phenotype. Electron microscopy of muscle from two cases revealed enlarged and accumulated mitochondria. Haplotype analysis performed in two unrelated families suggested that this variant is a result of recurrent mutation and not a founder effect. This suggests that p.(Arg247Gln) is associated with a relatively mild CMS phenotype with subtle mitochondrial abnormalities, while other variants in this gene cause more severe neurometabolic disease. In conclusion, the p.(Arg247Gln) SLC25A1 variant should be considered in patients presenting with a presynaptic CMS phenotype, particularly with accompanying intellectual disability.

}, keywords = {Adult, Female, Haplotypes, Homozygote, Humans, Intellectual Disability, Male, Mitochondrial Proteins, Muscle, Skeletal, Mutation, Missense, Myasthenic Syndromes, Congenital, Organic Anion Transporters}, issn = {1476-5438}, doi = {10.1038/s41431-019-0506-2}, author = {Balaraju, Sunitha and Topf, Ana and McMacken, Grace and Kumar, Veeramani Preethish and Pechmann, Astrid and Roper, Helen and Vengalil, Seena and Polavarapu, Kiran and Nashi, Saraswati and MAHjan, Niranjan Prakash and Barbosa, Ines A and Deshpande, Charu and Taylor, Robert W and Cossins, Judith and Beeson, David and Laurie, Steven and Kirschner, Janbernd and Horvath, Rita and McFarland, Robert and Nalini, Atchayaram and Lochm{\"u}ller, Hanns} } @article {951, title = { variants are associated with multiple congenital anomalies including ciliopathy phenotypes.}, journal = {J Med Genet}, year = {2020}, month = {2020 Jul 06}, abstract = {

BACKGROUND: Cilia are dynamic cellular extensions that generate and sense signals to orchestrate proper development and tissue homeostasis. They rely on the underlying polarisation of cells to participate in signalling. Cilia dysfunction is a well-known cause of several diseases that affect multiple organ systems including the kidneys, brain, heart, respiratory tract, skeleton and retina.

METHODS: Among individuals from four unrelated families, we identified variants in ( that manifested in a variety of pathologies. In our proband, we also examined patient tissues. We depleted in frog embryos to generate a loss-of-function model. Finally, we tested the pathogenicity of patient variants through rescue experiments in the frog model.

RESULTS: Patients with variants of were found to have a variety of phenotypes including cystic kidneys, nephrotic syndrome, hydrocephalus, limb abnormalities, congenital heart disease and craniofacial malformations. We also observed a loss of cilia in cystic kidney tissue of our proband. Knockdown of in embryos recapitulated many of these phenotypes and resulted in a loss of cilia in multiple tissues. Unlike introduction of wildtype in frog embryos depleted of introduction of patient variants was largely ineffective in restoring proper ciliation and tissue morphology in the kidney and brain suggesting that the variants were indeed detrimental to function.

CONCLUSION: These findings in both patient tissues and shed light on how mutations in may lead to tissue-specific manifestations of disease. DLG5 is essential for cilia and many of the patient phenotypes are in the ciliopathy spectrum.

}, issn = {1468-6244}, doi = {10.1136/jmedgenet-2019-106805}, author = {Marquez, Jonathan and Mann, Nina and Arana, Kathya and Deniz, Engin and Ji, Weizhen and Konstantino, Monica and Mis, Emily K and Deshpande, Charu and Jeffries, Lauren and McGlynn, Julie and Hugo, Hannah and Widmeier, Eugen and Konrad, Martin and Tasic, Velibor and Morotti, Raffaella and Baptista, Julia and Ellard, Sian and Lakhani, Saquib Ali and Hildebrandt, Friedhelm and Khokha, Mustafa K} }