@article {1001, title = {Loss of function mutations in GEMIN5 cause a neurodevelopmental disorder.}, journal = {Nat Commun}, volume = {12}, year = {2021}, month = {2021 05 07}, pages = {2558}, abstract = {

GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.

}, keywords = {Alleles, Amino Acid Sequence, Animals, Child, Preschool, Developmental Disabilities, Drosophila, Female, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Gene Ontology, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Loss of Function Mutation, Male, Muscle Hypotonia, Myoclonic Cerebellar Dyssynergia, Neurodevelopmental Disorders, Neurons, Pedigree, Polymorphism, Single Nucleotide, Ribonucleoproteins, Small Nuclear, Rigor Mortis, RNA-Seq, SMN Complex Proteins}, issn = {2041-1723}, doi = {10.1038/s41467-021-22627-w}, author = {Kour, Sukhleen and Rajan, Deepa S and Fortuna, Tyler R and Anderson, Eric N and Ward, Caroline and Lee, Youngha and Lee, Sangmoon and Shin, Yong Beom and Chae, Jong-Hee and Choi, Murim and Siquier, Karine and Cantagrel, Vincent and Amiel, Jeanne and Stolerman, Elliot S and Barnett, Sarah S and Cousin, Margot A and Castro, Diana and McDonald, Kimberly and Kirmse, Brian and Nemeth, Andrea H and Rajasundaram, Dhivyaa and Innes, A Micheil and Lynch, Danielle and Frosk, Patrick and Collins, Abigail and Gibbons, Melissa and Yang, Michele and Desguerre, Isabelle and Boddaert, Nathalie and Gitiaux, Cyril and Rydning, Siri Lynne and Selmer, Kaja K and Urreizti, Roser and Garcia-Oguiza, Alberto and Osorio, Andr{\'e}s Nascimento and Verdura, Edgard and Pujol, Aurora and McCurry, Hannah R and Landers, John E and Agnihotri, Sameer and Andriescu, E Corina and Moody, Shade B and Phornphutkul, Chanika and Sacoto, Maria J Guillen and Begtrup, Amber and Houlden, Henry and Kirschner, Janbernd and Schorling, David and Rudnik-Sch{\"o}neborn, Sabine and Strom, Tim M and Leiz, Steffen and Juliette, Kali and Richardson, Randal and Yang, Ying and Zhang, Yuehua and Wang, Minghui and Wang, Jia and Wang, Xiaodong and Platzer, Konrad and Donkervoort, Sandra and B{\"o}nnemann, Carsten G and Wagner, Matias and Issa, Mahmoud Y and Elbendary, Hasnaa M and Stanley, Valentina and Maroofian, Reza and Gleeson, Joseph G and Zaki, MAH S and Senderek, Jan and Pandey, Udai Bhan} } @article {945, title = {Biallelic in-frame deletion in TRAPPC4 in a family with developmental delay and cerebellar atrophy.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 10 01}, pages = {e83}, keywords = {Atrophy, Cerebellar Diseases, Humans, Intellectual Disability, Sequence Deletion}, issn = {1460-2156}, doi = {10.1093/brain/awaa256}, author = {Saad, Ahmed K and Marafi, Dana and Mitani, Tadahiro and Jolly, Angad and Du, Haowei and Elbendary, Hasnaa M and Jhangiani, Shalini N and Akdemir, Zeynep C and Gibbs, Richard A and Hunter, Jill V and Carvalho, Claudia M B C and Pehlivan, Davut and Posey, Jennifer E and Zaki, MAH S and Lupski, James R} } @article {806, title = {Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome.}, journal = {Am J Med Genet A}, volume = {182}, year = {2020}, month = {2020 10}, pages = {2272-2283}, abstract = {

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin-2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS-disease gene and expands its clinical and genetic spectrum to include recessive loss-of-function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.

}, keywords = {Adolescent, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Humans, Male, Muscle Hypotonia, Muscle Weakness, Mutation, Missense, Myasthenic Syndromes, Congenital, Pedigree, Phenotype, Synaptic Transmission, Synaptotagmin II}, issn = {1552-4833}, doi = {10.1002/ajmg.a.61765}, author = {Donkervoort, Sandra and Mohassel, Payam and Laugwitz, Lucia and Zaki, MAH S and Kamsteeg, Erik-Jan and Maroofian, Reza and Chao, Katherine R and Verschuuren-Bemelmans, Corien C and Horber, Veronka and Fock, Annemarie J M and McCarty, Riley M and Jain, Minal S and Biancavilla, Victoria and McMacken, Grace and Nalls, Matthew and Voermans, Nicol C and Elbendary, Hasnaa M and Snyder, Molly and Cai, Chunyu and Lehky, Tanya J and Stanley, Valentina and Iannaccone, Susan T and Foley, A Reghan and Lochm{\"u}ller, Hanns and Gleeson, Joseph and Houlden, Henry and Haack, Tobias B and Horvath, Rita and B{\"o}nnemann, Carsten G} } @article {826, title = {Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families.}, journal = {BMC Med Genomics}, volume = {13}, year = {2020}, month = {2020 05 13}, pages = {68}, abstract = {

BACKGROUND: The causes for thousands of individually rare recessive diseases have been discovered since the adoption of next generation sequencing (NGS). Following the molecular diagnosis in older children in a family, parents could use this information to opt for fetal genotyping in subsequent pregnancies, which could inform decisions about elective termination of pregnancy. The use of NGS diagnostic sequencing in families has not been demonstrated to yield benefit in subsequent pregnancies to reduce recurrence. Here we evaluated whether genetic diagnosis in older children in families supports reduction in recurrence of recessive neurogenetic disease.

METHODS: Retrospective study involving families with a child with a recessive pediatric brain disease (rPBD) that underwent NGS-based molecular diagnosis. Prenatal molecular testing was offered to couples in which a molecular diagnosis was made, to help couples seeking to prevent recurrence. With this information, families made decisions about elective termination. Pregnancies that were carried to term were assessed for the health of child and mother, and compared with historic recurrence risk of recessive disease.

RESULTS: Between 2010 and 2016, 1172 families presented with a child a likely~rPBD, 526 families received a molecular diagnosis, 91 families returned to the clinic with 101 subsequent pregnancies, and 84 opted for fetal genotyping. Sixty tested negative for recurrence for the biallelic mutation~in the fetus, and all, except for one spontaneous abortion, carried to term, and were unaffected at follow-up. Of 24 that genotyped positive~for~the biallelic mutation, 16 were electively terminated, and 8 were carried to term and showed features of disease similar to that of the older~affected sibling(s). Among the 101 pregnancies, disease recurrence in living offspring deviated from the expected 25\% to the observed 12\% ([95\% CI 0{\textperiodcentered}04 to 0{\textperiodcentered}20], p = 0{\textperiodcentered}011).

CONCLUSIONS: Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in subsequent pregnancies and genetic counselling, allows families to make informed decisions to reduce recessive neurogenetic disease recurrence.

}, keywords = {Child, Preschool, Female, Genes, Recessive, Genetic Markers, Genetic Predisposition to Disease, Genetic Testing, Genotype, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Mutation, Nervous System Diseases, Pedigree, Pregnancy, Prenatal Diagnosis, Recurrence, Retrospective Studies}, issn = {1755-8794}, doi = {10.1186/s12920-020-0714-1}, author = {Issa, Mahmoud Y and Chechlacz, Zinayida and Stanley, Valentina and George, Renee D and McEvoy-Venneri, Jennifer and Belandres, Denice and Elbendary, Hasnaa M and Gaber, Khaled R and Nabil, Ahmed and Abdel-Hamid, Mohamed S and Zaki, MAH S and Gleeson, Joseph G} } @article {500, title = {Genetic variants in components of the NALCN-UNC80-UNC79 ion channel complex cause a broad clinical phenotype (NALCN channelopathies).}, journal = {Hum Genet}, volume = {137}, year = {2018}, month = {2018 Sep}, pages = {753-768}, abstract = {

NALCN is a conserved cation channel, which conducts a permanent sodium leak current and regulates resting membrane potential and neuronal excitability. It is part of a large ion channel complex, the "NALCN channelosome", consisting of multiple proteins including UNC80 and UNC79. The predominant neuronal expression pattern and its function suggest an important role in neuronal function and disease. So far, biallelic NALCN and UNC80 variants have been described in a small number of individuals leading to infantile hypotonia, psychomotor retardation, and characteristic facies 1 (IHPRF1, OMIM 615419) and 2 (IHPRF2, OMIM 616801), respectively. Heterozygous de novo NALCN missense variants in the S5/S6 pore-forming segments lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD, OMIM 616266) with some clinical overlap. In this study, we present detailed clinical information of 16 novel individuals with biallelic NALCN variants, 1 individual with a heterozygous de novo NALCN missense variant and an interesting clinical phenotype without contractures, and 12 individuals with biallelic UNC80 variants. We report for the first time a missense NALCN variant~located in the predicted S6 pore-forming unit inherited in an autosomal-recessive manner leading to mild IHPRF1. We show evidence of clinical variability, especially among IHPRF1-affected individuals, and discuss differences between the IHPRF1- and IHPRF2 phenotypes. In summary, we provide a comprehensive overview of IHPRF1 and IHPRF2 phenotypes based on the largest cohort of individuals reported so far and provide additional insights into the clinical phenotypes of these neurodevelopmental diseases to help improve counseling of affected families.

}, keywords = {Adolescent, Adult, Carrier Proteins, Channelopathies, Child, Child, Preschool, Developmental Disabilities, Female, Genetic Markers, Genetic Variation, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Phenotype, Sodium Channels, Young Adult}, issn = {1432-1203}, doi = {10.1007/s00439-018-1929-5}, author = {Bramswig, Nuria C and Bertoli-Avella, Aida M and Albrecht, Beate and Al Aqeel, Aida I and Alhashem, Amal and Al-Sannaa, Nouriya and Bah, Maissa and Br{\"o}hl, Katharina and Depienne, Christel and Dorison, Nathalie and Doummar, Diane and Ehmke, Nadja and Elbendary, Hasnaa M and Gorokhova, Svetlana and H{\'e}ron, Delphine and Horn, Denise and James, Kiely and Keren, Boris and Kuechler, Alma and Ismail, Samira and Issa, Mahmoud Y and Marey, Isabelle and Mayer, Mich{\`e}le and McEvoy-Venneri, Jennifer and Megarbane, Andre and Mignot, Cyril and Mohamed, Sarar and Nava, Caroline and Philip, Nicole and Ravix, Cecile and Rolfs, Arndt and Sadek, Abdelrahim Abdrabou and Segebrecht, Lara and Stanley, Valentina and Trautman, Camille and Valence, Stephanie and Villard, Laurent and Wieland, Thomas and Engels, Hartmut and Strom, Tim M and Zaki, Maha S and Gleeson, Joseph G and L{\"u}decke, Hermann-Josef and Bauer, Peter and Wieczorek, Dagmar} }