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  1. Article ; Online: Unbiased mosaic variant assessment in sperm

    Martin W Breuss / Xiaoxu Yang / Valentina Stanley / Jennifer McEvoy-Venneri / Xin Xu / Arlene J Morales / Joseph G Gleeson

    eLife, Vol

    a cohort study to test predictability of transmission

    2022  Volume 11

    Abstract: Background: De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be ... ...

    Abstract Background: De novo mutations underlie individually rare but collectively common pediatric congenital disorders. Some of these mutations can also be detected in tissues and from cells in a parent, where their abundance and tissue distribution can be measured. We previously reported that a subset of these mutations is detectable in sperm from the father, predicted to impact the health of offspring. Methods: As a cohort study, in three independent couples undergoing in vitro fertilization, we first identified male gonadal mosaicism through deep whole genome sequencing. We then confirmed variants and assessed their transmission to preimplantation blastocysts (32 total) through targeted ultra-deep genotyping. Results: Across 55 gonadal mosaic variants, 15 were transmitted to blastocysts for a total of 19 transmission events. This represented an overall predictable but slight undertransmission based upon the measured mutational abundance in sperm. We replicated this conclusion in an independent, previously published family-based cohort. Conclusions: Unbiased preimplantation genetic testing for gonadal mosaicism may represent a feasible approach to reduce the transmission of potentially harmful de novo mutations. This—in turn—could help to reduce their impact on miscarriages and pediatric disease. Funding: No external funding was received for this work.
    Keywords sperm ; mosaicism ; de novo mutation ; blastocyst ; IVF ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 616
    Language English
    Publishing date 2022-07-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: INHERITED NEURODEVELOPMENTAL BRAIN DISEASES

    Joseph G. Gleeson

    Iranian Journal of Child Neurology, Vol 2, Iss 3, Pp 7-

    APPLICATIONS OF HOMOZYGOSITY MAPPING TO IDENTIFY NEW GENETIC CAUSES OF DISEASE

    2008  Volume 13

    Abstract: ObjectiveThe last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible to arrive ... ...

    Abstract ObjectiveThe last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible to arrive at a molecular diagnosis, due in part to lack of knowledge ofmolecular causes of these tremendously complex conditions. Common genetic disorders of brain development include septo-optic dysplasia, schizencephaly, holoprosencephaly, lissencephaly and hindbrain malformations. For each of these disorders, a critical step in brain development is disrupted. Specific genetic diagnosis is now possible in some patients with most of these conditions. For the remaining patients, it is possible to apply gene-mapping strategies using newly developed high-density genomic arrays to clone novel genes. This is especially important in countries like Iran where large family size and marriage between relatives makes these strategies tremendously powerful.
    Keywords Inherited Neurodevelopmental disease ; Microcephaly ; Joubert Syndrome ; Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; DOAJ:Neurology ; DOAJ:Medicine (General) ; DOAJ:Health Sciences ; Pediatrics ; RJ1-570 ; DOAJ:Pediatrics
    Subject code 610
    Language English
    Publishing date 2008-06-01T00:00:00Z
    Publisher Iranian Child Neurology Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: INHERITED NEURODEVELOPMENTAL BRAIN DISEASES

    Joseph G. Gleeson

    Iranian Journal of Child Neurology, Vol 2, Iss 3, Pp 7-

    APPLICATIONS OF HOMOZYGOSITY MAPPING TO IDENTIFY NEW GENETIC CAUSES OF DISEASE

    2008  Volume 13

    Abstract: Abstract Objective The last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible ... ...

    Abstract Abstract Objective The last two decades have seen major advancements in our understanding of some of the most common neurodevelopmental disorders in the field of child neurology. However, in the majority of individual patients, it is still not possible to arrive at a molecular diagnosis, due in part to lack of knowledge of molecular causes of these tremendously complex conditions. Common genetic disorders of brain development include septo-optic dysplasia, schizencephaly, holoprosencephaly, lissencephaly and hindbrain malformations. For each of these disorders, a critical step in brain development is disrupted. Specific genetic diagnosis is now possible in some patients with most of these conditions. For the remaining patients, it is possible to apply gene-mapping strategies using newly developed high-density genomic arrays to clone novel genes. This is especially important in countries like Iran where large family size and marriage between relatives makes these strategies tremendously powerful. Keywords: Inherited Neurodevelopmental disease, Microcephaly, Joubert Syndrome
    Keywords Neurology. Diseases of the nervous system ; RC346-429 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571 ; Internal medicine ; RC31-1245 ; Medicine ; R ; Pediatrics ; RJ1-570
    Subject code 600
    Language English
    Publishing date 2008-10-01T00:00:00Z
    Publisher Iranian Child Neurology Society
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder

    Raman Kumar / Mark A. Corbett / Nicholas J. C. Smith / Daniella H. Hock / Zoya Kikhtyak / Liana N. Semcesen / Atsushi Morimoto / Sangmoon Lee / David A. Stroud / Joseph G. Gleeson / Eric A. Haan / Jozef Gecz

    npj Genomic Medicine, Vol 7, Iss 1, Pp 1-

    2022  Volume 12

    Abstract: Abstract TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected ... ...

    Abstract Abstract TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug-resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice-switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility.
    Keywords Medicine ; R ; Genetics ; QH426-470
    Language English
    Publishing date 2022-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair

    Hana Hanzlikova / Evgeniia Prokhorova / Katerina Krejcikova / Zuzana Cihlarova / Ilona Kalasova / Jan Kubovciak / Jana Sachova / Richard Hailstone / Jan Brazina / Shereen Ghosh / Sebahattin Cirak / Joseph G. Gleeson / Ivan Ahel / Keith W. Caldecott

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 13

    Abstract: Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of ... ...

    Abstract Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of endogenous or exogenous DNA single-strand breaks.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair

    Hana Hanzlikova / Evgeniia Prokhorova / Katerina Krejcikova / Zuzana Cihlarova / Ilona Kalasova / Jan Kubovciak / Jana Sachova / Richard Hailstone / Jan Brazina / Shereen Ghosh / Sebahattin Cirak / Joseph G. Gleeson / Ivan Ahel / Keith W. Caldecott

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 13

    Abstract: Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of ... ...

    Abstract Defects in DNA single-strand break repair are associated with neurodegenerative disease. Here the authors reveal that mutations in ARH3 interfere with the catabolism of mono-(ADP-ribose) and lead to its accumulation on core histones following repair of endogenous or exogenous DNA single-strand breaks.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: Author Correction

    Lu Wang / Zhen Li / David Sievert / Desirée E. C. Smith / Marisa I. Mendes / Dillon Y. Chen / Valentina Stanley / Shereen Ghosh / Yulu Wang / Majdi Kara / Ayca Dilruba Aslanger / Rasim O. Rosti / Henry Houlden / Gajja S. Salomons / Joseph G. Gleeson

    Nature Communications, Vol 12, Iss 1, Pp 1-

    Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

    2021  Volume 4

    Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21448- ... ...

    Abstract A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21448-1
    Keywords Science ; Q
    Language English
    Publishing date 2021-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

    Lu Wang / Zhen Li / David Sievert / Desirée E. C. Smith / Marisa I. Mendes / Dillon Y. Chen / Valentina Stanley / Shereen Ghosh / Yulu Wang / Majdi Kara / Ayca Dilruba Aslanger / Rasim O. Rosti / Henry Houlden / Gajja S. Salomons / Joseph G. Gleeson

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 12

    Abstract: Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly ... ...

    Abstract Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly characteristics and scRNA-seq reveals a role for NARS1 in radial glial cell proliferation.
    Keywords Science ; Q
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly

    Lu Wang / Zhen Li / David Sievert / Desirée E. C. Smith / Marisa I. Mendes / Dillon Y. Chen / Valentina Stanley / Shereen Ghosh / Yulu Wang / Majdi Kara / Ayca Dilruba Aslanger / Rasim O. Rosti / Henry Houlden / Gajja S. Salomons / Joseph G. Gleeson

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 12

    Abstract: Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly ... ...

    Abstract Asparaginyl-tRNA synthetase1 (NARS1) is required for protein synthesis. Here, the authors identify biallelic NARS1 mutations in individuals with microcephaly and neurodevelopmental delay. Cortical brain organoid modeling recapitulates microcephaly characteristics and scRNA-seq reveals a role for NARS1 in radial glial cell proliferation.
    Keywords Science ; Q
    Language English
    Publishing date 2020-08-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  10. Article ; Online: Molecular diagnosis in recessive pediatric neurogenetic disease can help reduce disease recurrence in families

    Mahmoud Y. Issa / Zinayida Chechlacz / Valentina Stanley / Renee D. George / Jennifer McEvoy-Venneri / Denice Belandres / Hasnaa M. Elbendary / Khaled R. Gaber / Ahmed Nabil / Mohamed S. Abdel-Hamid / Maha S. Zaki / Joseph G. Gleeson

    BMC Medical Genomics, Vol 13, Iss 1, Pp 1-

    2020  Volume 10

    Abstract: 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 ... ...

    Abstract 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 0·04 to 0·20], p = 0·011). Conclusions Molecular diagnosis in an older child, coupled with prenatal fetal genotyping in ...
    Keywords Internal medicine ; RC31-1245 ; Genetics ; QH426-470
    Subject code 610
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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