@article {637, title = {Clinically severe CACNA1A alleles affect synaptic function and neurodegeneration differentially.}, journal = {PLoS Genet}, volume = {13}, year = {2017}, month = {2017 Jul}, pages = {e1006905}, abstract = {

Dominant mutations in CACNA1A, encoding the α-1A subunit of the neuronal P/Q type voltage-dependent Ca2+ channel, can cause diverse neurological phenotypes. Rare cases of markedly severe early onset developmental delay and congenital ataxia can be due to de novo CACNA1A missense alleles, with variants affecting the S4 transmembrane segments of the channel, some of which are reported to be loss-of-function. Exome sequencing in five individuals with severe early onset ataxia identified one novel variant (p.R1673P), in a girl with global developmental delay and progressive cerebellar atrophy, and a recurrent, de novo p.R1664Q variant, in four individuals with global developmental delay, hypotonia, and ophthalmologic abnormalities. Given the severity of these phenotypes we explored their functional impact in Drosophila. We previously generated null and partial loss-of-function alleles of cac, the homolog of CACNA1A in Drosophila. Here, we created transgenic wild type and mutant genomic rescue constructs with the two noted conserved point mutations. The p.R1673P mutant failed to rescue cac lethality, displayed a gain-of-function phenotype in electroretinograms (ERG) recorded from mutant clones, and evolved a neurodegenerative phenotype in aging flies, based on ERGs and transmission electron microscopy. In contrast, the p.R1664Q variant exhibited loss of function and failed to develop a neurodegenerative phenotype. Hence, the novel R1673P allele produces neurodegenerative phenotypes in flies and human, likely due to a toxic gain of function.

}, keywords = {Alleles, Animals, Animals, Genetically Modified, Calcium Channels, Cerebellar Ataxia, Child, Child, Preschool, Drosophila melanogaster, Female, Genome, Human, Genome-Wide Association Study, Humans, Male, Microscopy, Electron, Transmission, Mutation, Missense, Neurodegenerative Diseases, Neuroimaging, Phenotype, Point Mutation}, issn = {1553-7404}, doi = {10.1371/journal.pgen.1006905}, author = {Luo, Xi and Rosenfeld, Jill A and Yamamoto, Shinya and Harel, Tamar and Zuo, Zhongyuan and Hall, Melissa and Wierenga, Klaas J and Pastore, Matthew T and Bartholomew, Dennis and Delgado, Mauricio R and Rotenberg, Joshua and Lewis, Richard Alan and Emrick, Lisa and Bacino, Carlos A and Eldomery, Mohammad K and Coban Akdemir, Zeynep and Xia, Fan and Yang, Yaping and Lalani, Seema R and Lotze, Timothy and Lupski, James R and Lee, Brendan and Bellen, Hugo J and Wangler, Michael F} } @article {424, title = {De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder.}, journal = {Am J Hum Genet}, volume = {101}, year = {2017}, month = {2017 Nov 02}, pages = {716-724}, abstract = {

DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in~vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.

}, keywords = {Adenosine Triphosphatases, Adolescent, Amino Acids, Cell Line, Cell Line, Tumor, Central Nervous System, Child, Child, Preschool, Developmental Disabilities, Female, HEK293 Cells, Humans, Intellectual Disability, Male, Mutation, Missense, RNA, RNA Helicases}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.09.014}, author = {Lessel, Davor and Schob, Claudia and K{\"u}ry, S{\'e}bastien and Reijnders, Margot R F and Harel, Tamar and Eldomery, Mohammad K and Coban-Akdemir, Zeynep and Denecke, Jonas and Edvardson, Shimon and Colin, Estelle and Stegmann, Alexander P A and Gerkes, Erica H and Tessarech, Marine and Bonneau, Dominique and Barth, Magalie and Besnard, Thomas and Cogn{\'e}, Benjamin and Revah-Politi, Anya and Strom, Tim M and Rosenfeld, Jill A and Yang, Yaping and Posey, Jennifer E and Immken, LaDonna and Oundjian, Nelly and Helbig, Katherine L and Meeks, Naomi and Zegar, Kelsey and Morton, Jenny and Schieving, Jolanda H and Claasen, Ana and Huentelman, Matthew and Narayanan, Vinodh and Ramsey, Keri and Brunner, Han G and Elpeleg, Orly and Mercier, Sandra and B{\'e}zieau, St{\'e}phane and Kubisch, Christian and Kleefstra, Tjitske and Kindler, Stefan and Lupski, James R and Kreienkamp, Hans-J{\"u}rgen} } @article {75, title = {Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.}, journal = {Am J Hum Genet}, volume = {98}, year = {2016}, month = {2016 Mar 03}, pages = {562-570}, abstract = {

The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from nonsense-mediated decay. Using whole-exome sequencing, we identified homozygous variants in EMC1 that segregated with a phenotype of developmental delay, hypotonia, scoliosis, and cerebellar atrophy in three families. In addition, a de novo heterozygous EMC1 variant was seen in an individual with a similar clinical and MRI imaging phenotype. EMC1 encodes a member of the endoplasmic reticulum (ER)-membrane protein complex (EMC), an evolutionarily conserved complex that has been proposed to have multiple roles in ER-associated degradation, ER-mitochondria tethering, and proper assembly of multi-pass transmembrane proteins. Perturbations of protein folding and organelle crosstalk have been implicated in neurodegenerative processes including cerebellar atrophy. We propose EMC1 as a gene in which either biallelic or monoallelic variants might lead to a syndrome including intellectual disability and preferential degeneration of the cerebellum.

}, keywords = {Adolescent, Alleles, Amino Acid Sequence, Atrophy, Cerebellum, Child, Child, Preschool, Developmental Disabilities, Endoplasmic Reticulum-Associated Degradation, Female, Genetic Association Studies, Genetic Variation, Heterozygote, Humans, Magnetic Resonance Imaging, Male, Molecular Sequence Data, Muscle Hypotonia, Mutation, Pedigree, Protein Folding, Proteins, Scoliosis}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.01.011}, author = {Harel, Tamar and Yesil, G{\"o}zde and Bayram, Yavuz and Coban-Akdemir, Zeynep and Charng, Wu-Lin and Karaca, Ender and Al Asmari, Ali and Eldomery, Mohammad K and Hunter, Jill V and Jhangiani, Shalini N and Rosenfeld, Jill A and Pehlivan, Davut and El-Hattab, Ayman W and Saleh, Mohammed A and LeDuc, Charles A and Muzny, Donna and Boerwinkle, Eric and Gibbs, Richard A and Chung, Wendy K and Yang, Yaping and Belmont, John W and Lupski, James R} } @article {41, title = {Nonrecurrent PMP22-RAI1 contiguous gene deletions arise from replication-based mechanisms and result in Smith-Magenis syndrome with evident peripheral neuropathy.}, journal = {Hum Genet}, volume = {135}, year = {2016}, month = {2016 Oct}, pages = {1161-74}, abstract = {

Hereditary neuropathy with liability to pressure palsies (HNPP) and Smith-Magenis syndrome (SMS) are genomic disorders associated with deletion copy number variants involving chromosome 17p12 and 17p11.2, respectively. Nonallelic homologous recombination (NAHR)-mediated recurrent deletions are responsible for the majority of HNPP and SMS cases; the rearrangement products encompass the key dosage-sensitive genes PMP22 and RAI1, respectively, and result in haploinsufficiency for these genes. Less frequently, nonrecurrent genomic rearrangements occur at this locus. Contiguous gene duplications encompassing both PMP22 and RAI1, i.e., PMP22-RAI1 duplications, have been investigated, and replication-based mechanisms rather than NAHR have been proposed for these rearrangements. In the current study, we report molecular and clinical characterizations of six subjects with the reciprocal phenomenon of deletions spanning both genes, i.e., PMP22-RAI1 deletions. Molecular studies utilizing high-resolution array comparative genomic hybridization and breakpoint junction sequencing identified mutational signatures that were suggestive of replication-based mechanisms. Systematic clinical studies revealed features consistent with SMS, including features of intellectual disability, speech and gross motor delays, behavioral problems and ocular abnormalities. Five out of six subjects presented clinical signs and/or objective electrophysiologic studies of peripheral neuropathy. Clinical profiling may improve the clinical management of this unique group of subjects, as the peripheral neuropathy can be more severe or of earlier onset as compared to SMS patients having the common recurrent deletion. Moreover, the current study, in combination with the previous report of PMP22-RAI1 duplications, contributes to the understanding of rare complex phenotypes involving multiple dosage-sensitive genes from a genetic mechanistic standpoint.

}, keywords = {Adolescent, Adult, Child, Child, Preschool, Chromosomes, Human, Pair 17, DNA Copy Number Variations, DNA Replication, Female, Gene Deletion, Haploinsufficiency, Homologous Recombination, Humans, Intellectual Disability, Male, Mutation, Myelin Proteins, Smith-Magenis Syndrome, Trans-Activators, Transcription Factors}, issn = {1432-1203}, doi = {10.1007/s00439-016-1703-5}, author = {Yuan, Bo and Neira, Juanita and Gu, Shen and Harel, Tamar and Liu, Pengfei and Brice{\~n}o, Ignacio and Elsea, Sarah H and G{\'o}mez, Alberto and Potocki, Lorraine and Lupski, James R} } @article {97, title = {POGZ truncating alleles cause syndromic intellectual disability.}, journal = {Genome Med}, volume = {8}, year = {2016}, month = {2016 Jan 06}, pages = {3}, abstract = {

BACKGROUND: Large-scale cohort-based whole exome sequencing of individuals with neurodevelopmental disorders (NDDs) has identified numerous novel candidate disease genes; however, detailed phenotypic information is often lacking in such studies. De novo mutations in pogo transposable element with zinc finger domain (POGZ) have been identified in six independent and diverse cohorts of individuals with NDDs ranging from autism spectrum disorder to developmental delay.

METHODS: Whole exome sequencing was performed on five unrelated individuals. Sanger sequencing was used to validate variants and segregate mutations with the phenotype in available family members.

RESULTS: We identified heterozygous truncating mutations in POGZ in five unrelated individuals, which were confirmed to be de novo or not present in available parental samples. Careful review of the phenotypes revealed shared features that included developmental delay, intellectual disability, hypotonia, behavioral abnormalities, and similar facial characteristics. Variable features included short stature, microcephaly, strabismus and hearing loss.

CONCLUSIONS: While POGZ has been associated with neurodevelopmental disorders in large cohort studies, our data suggest that loss of function variants in POGZ lead to an identifiable syndrome of NDD with specific phenotypic traits. This study exemplifies the era of human reverse clinical genomics ushered in by large disease-directed cohort studies; first defining a new syndrome molecularly and, only subsequently, phenotypically.

}, keywords = {Adolescent, Adult, Alleles, Child, Preschool, Exome, Female, Heterozygote, Humans, Infant, Intellectual Disability, Male, Mutation, Sequence Analysis, DNA, Transposases}, issn = {1756-994X}, doi = {10.1186/s13073-015-0253-0}, author = {White, Janson and Beck, Christine R and Harel, Tamar and Posey, Jennifer E and Jhangiani, Shalini N and Tang, Sha and Farwell, Kelly D and Powis, Z{\"o}e and Mendelsohn, Nancy J and Baker, Janice A and Pollack, Lynda and Mason, Kati J and Wierenga, Klaas J and Arrington, Daniel K and Hall, Melissa and Psychogios, Apostolos and Fairbrother, Laura and Walkiewicz, Magdalena and Person, Richard E and Niu, Zhiyv and Zhang, Jing and Rosenfeld, Jill A and Muzny, Donna M and Eng, Christine and Beaudet, Arthur L and Lupski, James R and Boerwinkle, Eric and Gibbs, Richard A and Yang, Yaping and Xia, Fan and Sutton, V Reid} } @article {21, title = {Recurrent De Novo and Biallelic Variation of ATAD3A, Encoding a Mitochondrial Membrane Protein, Results in Distinct Neurological Syndromes.}, journal = {Am J Hum Genet}, volume = {99}, year = {2016}, month = {2016 Oct 06}, pages = {831-845}, abstract = {

ATPase family AAA-domain containing protein 3A (ATAD3A) is a nuclear-encoded mitochondrial membrane protein implicated in mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. We identified a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing (WES) in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy. We also describe two families with biallelic variants in ATAD3A, including a homozygous variant in two siblings, and biallelic ATAD3A deletions mediated by nonallelic homologous recombination (NAHR) between ATAD3A and gene family members ATAD3B and ATAD3C. Tissue-specific overexpression of bor, the Drosophila mutation homologous to the human c.1582C>T (p.Arg528Trp) variant, resulted in a dramatic decrease in mitochondrial content, aberrant mitochondrial morphology, and increased autophagy. Homozygous null bor larvae showed a significant decrease of mitochondria, while overexpression of bor resulted in larger, elongated mitochondria. Finally, fibroblasts of an affected individual exhibited increased mitophagy. We conclude that the p.Arg528Trp variant functions through a dominant-negative mechanism that results in small mitochondria that trigger mitophagy, resulting in a reduction in mitochondrial content. ATAD3A variation represents an additional link between mitochondrial dynamics and recognizable neurological syndromes, as seen with MFN2, OPA1, DNM1L, and STAT2 mutations.

}, keywords = {Adenosine Triphosphatases, Adult, Alleles, Animals, ATPases Associated with Diverse Cellular Activities, Axons, Cardiomyopathies, Child, Child, Preschool, Developmental Disabilities, DNA Copy Number Variations, Drosophila melanogaster, Female, Fibroblasts, Homozygote, Humans, Infant, Infant, Newborn, Male, Membrane Proteins, Mitochondria, Mitochondrial Proteins, Muscle Hypotonia, Muscles, Mutation, Nervous System Diseases, Neurons, Optic Atrophy, Phenotype, Polymorphism, Single Nucleotide, Syndrome, Young Adult}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2016.08.007}, author = {Harel, Tamar and Yoon, Wan Hee and Garone, Caterina and Gu, Shen and Coban-Akdemir, Zeynep and Eldomery, Mohammad K and Posey, Jennifer E and Jhangiani, Shalini N and Rosenfeld, Jill A and Cho, Megan T and Fox, Stephanie and Withers, Marjorie and Brooks, Stephanie M and Chiang, Theodore and Duraine, Lita and Erdin, Serkan and Yuan, Bo and Shao, Yunru and Moussallem, Elie and Lamperti, Costanza and Donati, Maria A and Smith, Joshua D and McLaughlin, Heather M and Eng, Christine M and Walkiewicz, Magdalena and Xia, Fan and Pippucci, Tommaso and Magini, Pamela and Seri, Marco and Zeviani, Massimo and Hirano, Michio and Hunter, Jill V and Srour, Myriam and Zanigni, Stefano and Lewis, Richard Alan and Muzny, Donna M and Lotze, Timothy E and Boerwinkle, Eric and Gibbs, Richard A and Hickey, Scott E and Graham, Brett H and Yang, Yaping and Buhas, Daniela and Martin, Donna M and Potocki, Lorraine and Graziano, Claudio and Bellen, Hugo J and Lupski, James R} } @article {345, title = {The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy.}, journal = {Genet Med}, volume = {18}, year = {2016}, month = {2016 05}, pages = {443-51}, abstract = {

PURPOSE: Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders of the peripheral nervous system. Copy-number variants (CNVs) contribute significantly to CMT, as duplication of PMP22 underlies the majority of CMT1 cases. We hypothesized that CNVs and/or single-nucleotide variants (SNVs) might exist in patients with CMT with an unknown molecular genetic etiology.

METHODS: Two hundred patients with CMT, negative for both SNV mutations in several CMT genes and for CNVs involving PMP22, were screened for CNVs by high-resolution oligonucleotide array comparative genomic hybridization. Whole-exome sequencing was conducted on individuals with rare, potentially pathogenic CNVs.

RESULTS: Putatively causative CNVs were identified in five subjects (~2.5\%); four of the five map to known neuropathy genes. Breakpoint sequencing revealed Alu-Alu-mediated junctions as a predominant contributor. Exome sequencing identified MFN2 SNVs in two of the individuals.

CONCLUSION: Neuropathy-associated CNV outside of the PMP22 locus is rare in CMT. Nevertheless, there is potential clinical utility in testing for CNVs and exome sequencing in CMT cases negative for the CMT1A duplication. These findings suggest that complex phenotypes including neuropathy can potentially be caused by a combination of SNVs and CNVs affecting more than one disease-associated locus and contributing to a mutational burden.Genet Med 18 5, 443-451.

}, keywords = {Adult, Age of Onset, Charcot-Marie-Tooth Disease, Child, Preschool, Comparative Genomic Hybridization, DNA Copy Number Variations, Exome, Female, Genetic Predisposition to Disease, GTP Phosphohydrolases, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Motor Neurons, Myelin P0 Protein, Myelin Proteins, Neural Conduction, Polymorphism, Single Nucleotide, Polyneuropathies}, issn = {1530-0366}, doi = {10.1038/gim.2015.124}, author = {Pehlivan, Davut and Beck, Christine R and Okamoto, Yuji and Harel, Tamar and Akdemir, Zeynep H C and Jhangiani, Shalini N and Withers, Marjorie A and Goksungur, Meryem Tuba and Carvalho, Claudia M B and Czesnik, Dirk and Gonzaga-Jauregui, Claudia and Wiszniewski, Wojciech and Muzny, Donna M and Gibbs, Richard A and Rautenstrauss, Bernd and Sereda, Michael W and Lupski, James R} } @article {120, title = {Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.}, journal = {Am J Hum Genet}, volume = {97}, year = {2015}, month = {2015 Nov 05}, pages = {691-707}, abstract = {

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.

}, keywords = {Abnormalities, Multiple, Charcot-Marie-Tooth Disease, Child, Child, Preschool, Chromosome Disorders, Chromosome Duplication, Chromosomes, Human, Pair 17, Comparative Genomic Hybridization, Female, Follow-Up Studies, Gene Duplication, Gene Rearrangement, Genome, Human, Genomics, Humans, Infant, Male, Models, Genetic, Myelin Proteins, Phenotype, Prognosis, Recombination, Genetic, Transcription Factors}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2015.10.003}, author = {Yuan, Bo and Harel, Tamar and Gu, Shen and Liu, Pengfei and Burglen, Lydie and Chantot-Bastaraud, Sandra and Gelowani, Violet and Beck, Christine R and Carvalho, Claudia M B and Cheung, Sau Wai and Coe, Andrew and Malan, Val{\'e}rie and Munnich, Arnold and Magoulas, Pilar L and Potocki, Lorraine and Lupski, James R} }