Scientific Publications

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31 Results


Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders

Gillentine MA, Wang T, Hoekzema K, Rosenfeld J, Liu P, Guo H, Kim CN, De Vries BBA, Vissers LELM, Nordenskjold M, Kvarnung M, Lindstrand A, Nordgren A, Gecz J, Iascone M, Cereda A, Scatigno A, Maitz S, Zanni G, Bertini E, Zweier C, Schuhmann S, Wiesener A, Pepper M, Panjwani H, Torti E, Abid F, Anselm I, Srivastava S, Atwal P, Bacino CA, Bhat G, Cobian K, Bird LM, Friedman J, Wright MS, Callewaert B, Petit F, Mathieu S, Afenjar A, Christensen CK, White KM, Elpeleg O, Berger I, Espineli EJ, Fagerberg C, Brasch-Andersen C, Hansen LK, Feyma T, Hughes S, Thiffault I, Sullivan B, Yan S, Keller K, Keren B, Mignot C, Kooy F, Meuwissen M, Basinger A, Kukolich M, Philips M, Ortega L, Drummond-Borg M, Lauridsen M, Sorensen K, Lehman A; CAUSES Study, Lopez-Rangel E, Levy P, Lessel D, Lotze T, Madan-Khetarpal S, Sebastian J, Vento J, Vats D, Benman LM, Mckee S, Mirzaa GM, Muss C, Pappas J, Peeters H, Romano C, Elia M, Galesi O, Simon MEH, van Gassen KLI, Simpson K, Stratton R, Syed S, Thevenon J, Palafoll IV, Vitobello A, Bournez M, Faivre L, Xia K; SPARK Consortium, Earl RK, Nowakowski T, Bernier RA, Eichler EE.

Madelyn A Gillentine Genome Med. 2021 Apr 19;13(1):63. doi: 10.1186/s13073-021-00870-6. ABSTRACT BACKGROUND: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. METHODS: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. RESULTS: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. CONCLUSIONS: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics. PMID:33874999   DOI:10.1186/s13073-021-00870-6

April 20, 2021
Gene DiscoveryGenetic Neurologic DiseaseNeurogenomics

Biallelic hypomorphic mutations in HEATR5B, encoding HEAT repeat-containing protein 5B, in a neurological syndrome with pontocerebellar hypoplasia

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG.

Eur J Hum Genet. 2021 Apr 6. doi: 10.1038/s41431-021-00832-x. Online ahead of print.


HEAT repeats are 37-47 amino acid flexible tandem repeat structural motifs occurring in a wide variety of eukaryotic proteins with diverse functions. Due to their ability to undergo elastic conformational changes, they often serve as scaffolds at sites of protein interactions. Here, we describe four affected children from two families presenting with pontocerebellar hypoplasia manifest clinically with neonatal seizures, severe intellectual disability, and motor delay. Whole exome sequencing identified biallelic variants at predicted splice sites in intron 31 of HEATR5B, encoding the HEAT repeat-containing protein 5B segregating in a recessive fashion. Aberrant splicing was found in patient fibroblasts, which correlated with reduced levels of HEATR5B protein. HEATR5B is expressed during brain development in human, and we failed to recover live-born homozygous Heatr5b knockout mice. Taken together, our results implicate loss of HEATR5B in pontocerebellar hypoplasia.

PMID:33824466 | DOI:10.1038/s41431-021-00832-x

April 7, 2021

Comprehensive identification of somatic nucleotide variants in human brain tissue

Wang Y, Bae T, Thorpe J, Sherman MA, Jones AG, Cho S, Daily K, Dou Y, Ganz J, Galor A, Lobon I, Pattni R, Rosenbluh C, Tomasi S, Tomasini L, Yang X, Zhou B, Akbarian S, Ball LL, Bizzotto S, Emery SB, Doan R, Fasching L, Jang Y, Juan D, Lizano E, Luquette LJ, Moldovan JB, Narurkar R, Oetjens MT, Rodin RE, Sekar S, Shin JH, Soriano E, Straub RE, Zhou W, Chess A, Gleeson JG, Marquès-Bonet T, Park PJ, Peters MA, Pevsner J, Walsh CA, Weinberger DR; Brain Somatic Mosaicism Network, Vaccarino FM, Moran JV, Urban AE, Kidd JM, Mills RE, Abyzov A.

Genome Biol. 2021 Mar 29;22(1):92. doi: 10.1186/s13059-021-02285-3. ABSTRACT BACKGROUND: Post-zygotic mutations incurred during DNA replication, DNA repair, and other cellular processes lead to somatic mosaicism. Somatic mosaicism is an established cause of various diseases, including cancers. However, detecting mosaic variants in DNA from non-cancerous somatic tissues poses significant challenges, particularly if the variants only are present in a small fraction of cells. RESULTS: Here, the Brain Somatic Mosaicism Network conducts a coordinated, multi-institutional study to examine the ability of existing methods to detect simulated somatic single-nucleotide variants (SNVs) in DNA mixing experiments, generate multiple replicates of whole-genome sequencing data from the dorsolateral prefrontal cortex, other brain regions, dura mater, and dural fibroblasts of a single neurotypical individual, devise strategies to discover somatic SNVs, and apply various approaches to validate somatic SNVs. These efforts lead to the identification of 43 bona fide somatic SNVs that range in variant allele fractions from ~ 0.005 to ~ 0.28. Guided by these results, we devise best practices for calling mosaic SNVs from 250× whole-genome sequencing data in the accessible portion of the human genome that achieve 90% specificity and sensitivity. Finally, we demonstrate that analysis of multiple bulk DNA samples from a single individual allows the reconstruction of early developmental cell lineage trees. CONCLUSIONS: This study provides a unified set of best practices to detect somatic SNVs in non-cancerous tissues. The data and methods are freely available to the scientific community and should serve as a guide to assess the contributions of somatic SNVs to neuropsychiatric diseases. PMID:33781308 | PMC:PMC8006362 | DOI:10.1186/s13059-021-02285-3

March 30, 2021

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

Ghosh SG, Breuss MW, Schlachetzki Z, Chai G, Ross D, Stanley V, Sonmez FM, Topaloglu H, Zaki MS, Hosny H, Gad S, Gleeson JG.

Nat Commun. 2021 Feb 15;12(1):1192. doi: 10.1038/s41467-021-21448-1.


PMID:33589599 | PMC:PMC7884391 | DOI:10.1038/s41467-021-21448-1

February 16, 2021

Expanding the phenotype of PIGS-associated early onset epileptic developmental encephalopathy

Efthymiou S, Dutra-Clarke M, Maroofian R, Kaiyrzhanov R, Scala M, Reza Alvi J, Sultan T, Christoforou M, Tuyet Mai Nguyen T, Mankad K, Vona B, Rad A, Striano P, Salpietro V, Guillen Sacoto MJ, Zaki MS, Gleeson JG, Campeau PM, Russell BE, Houlden H.

Epilepsia. 2021 Feb;62(2):e35-e41. doi: 10.1111/epi.16801. Epub 2021 Jan 7. ABSTRACT The phosphatidylinositol glycan anchor biosynthesis class S protein (PIGS) gene has recently been implicated in a novel congenital disorder of glycosylation resulting in autosomal recessive inherited glycosylphosphatidylinositol-anchored protein (GPI-AP) deficiency. Previous studies described seven patients with biallelic variants in the PIGS gene, of whom two presented with fetal akinesia and five with global developmental delay and epileptic developmental encephalopathy. We present the molecular and clinical characteristics of six additional individuals from five families with unreported variants in PIGS. All individuals presented with hypotonia, severe global developmental delay, microcephaly, intractable early infantile epilepsy, and structural brain abnormalities. Additional findings include vision impairment, hearing loss, renal malformation, and hypotonic facial appearances with minor dysmorphic features but without a distinctive facial gestalt. Four individuals died due to neurologic complications. GPI anchoring studies performed on one individual revealed a significant decrease in GPI-APs. We confirm that biallelic variants in PIGS cause vitamin pyridoxine-responsive epilepsy due to inherited GPI deficiency and expand the genotype and phenotype of PIGS-related disorder. Further delineation of the molecular spectrum of PIGS-related disorders would improve management, help develop treatments, and encourage the expansion of diagnostic genetic testing to include this gene as a potential cause of neurodevelopmental disorders and epilepsy. PMID:33410539 | PMC:PMC7898547 | DOI:10.1111/epi.16801

January 7, 2021


Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly

Chai G, Webb A, Li C, Antaki D, Lee S, Breuss MW, Lang N, Stanley V, Anzenberg P, Yang X, Marshall T, Gaffney P, Wierenga KJ, Chung BH, Tsang MH, Pais LS, Lovgren AK, VanNoy GE, Rehm HL, Mirzaa G, Leon E, Diaz J, Neumann A, Kalverda AP, Manfield IW, Parry DA, Logan CV, Johnson CA, Bonthron DT, Valleley EMA, Issa MY, Abdel-Ghafar SF, Abdel-Hamid MS, Jennings P, Zaki MS, Sheridan E, Gleeson JG.

Neuron. 2021 Jan 20;109(2):241-256.e9. doi: 10.1016/j.neuron.2020.10.035. Epub 2020 Nov 20.


Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and “major spliceosome-opathies” as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

PMID:33220177 | DOI:10.1016/j.neuron.2020.10.035

November 21, 2020

Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition

Ghosh SG, Lee S, Fabunan R, Chai G, Zaki MS, Abdel-Salam G, Sultan T, Ben-Omran T, Alvi JR, McEvoy-Venneri J, Stanley V, Patel A, Ross D, Ding J, Jain M, Pan D, Lübbert P, Kammerer B, Wiedemann N, Verhoeven-Duif NM, Jans JJ, Murphy D, Toosi MB, Ashrafzadeh F, Imannezhad S, Karimiani EG, Ibrahim K, Waters ER, Maroofian R, Gleeson JG.

Genet Med. 2021 Mar;23(3):524-533. doi: 10.1038/s41436-020-01010-y. Epub 2020 Nov 14.


PURPOSE: Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown.

METHODS: We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD.

RESULTS: We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways.

CONCLUSION: The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

PMID:33188300 | DOI:10.1038/s41436-020-01010-y

November 14, 2020

Editorial overview: Neurodevelopment Diseases and Neurogenetics pivot towards mechanisms and therapies

Geschwind DH, Gleeson JG.

Curr Opin Genet Dev. 2020 Dec;65:iii-vii. doi: 10.1016/j.gde.2020.09.001. Epub 2020 Nov 8. NO ABSTRACT PMID:33176916 | DOI:10.1016/j.gde.2020.09.001

November 12, 2020

A founder mutation in PEX12 among Egyptian patients in peroxisomal biogenesis disorder

Zaki MS, Issa MY, Thomas MM, Elbendary HM, Rafat K, Al Menabawy NM, Selim LA, Ismail S, Abdel-Salam GM, Gleeson JG. 

Neurol Sci. 2020 Oct 29. doi: 10.1007/s10072-020-04843-2. Online ahead of print. ABSTRACT At least 14 distinctive PEX genes function in the biogenesis of peroxisomes. Biallelic alterations in the peroxisomal biogenesis factor 12 (PEX12) gene lead to Zellweger syndrome spectrum (ZSS) with variable clinical expressivity ranging from early lethality to mildly affected with long-term survival. Herein, we define 20 patients derived from 14 unrelated Egyptian families, 19 of which show a homozygous PEX12 in-frame (c.1047_1049del p.(Gln349del)) deletion. This founder mutation, reported rarely outside of Egypt, was associated with a uniformly severe phenotype. Patients showed developmental delay in early life followed by motor and mental regression, progressive hypotonia, unsteadiness, and lack of speech. Seventeen patients had sparse hair or partial alopecia, a striking feature that was not noted previously in PEX12. Neonatal cholestasis was manifested in 2 siblings. Neurodiagnostics showed consistent cerebellar atrophy and variable white matter demyelination, axonal neuropathy in about half, and cardiomyopathy in 10% of patients. A single patient with a compound heterozygous PEX12 mutation exhibited milder features with late childhood onset with gait disturbance and learning disability. Thus, the PEX12 relatively common founder mutation accounts for the majority of PEX12-related disease in Egypt and delineates a uniform clinical and radiographic phenotype. PMID:33123925 | DOI:10.1007/s10072-020-04843-2

October 30, 2020

Insight into developmental mechanisms of global and focal migration disorders of cortical development

Castello MA, Gleeson JG. 

Curr Opin Neurobiol. 2020 Oct 21;66:77-84. doi: 10.1016/j.conb.2020.10.005. Online ahead of print. ABSTRACT Cortical development involves neurogenesis followed by migration, maturation, and myelination of immature neurons. Disruptions in these processes can cause malformations of cortical development (MCD). Radial glia (RG) are the stem cells of the brain, both generating neurons and providing the scaffold upon which immature neurons radially migrate. Germline mutations in genes required for cell migration, or cell-cell contact, often lead to global MCDs. Somatic mutations in RG in genes involved in homeostatic function, like mTOR signaling, often lead to focal MCDs. Two different mutations occurring in the same patient can combine in ways we are just beginning to understand. Our growing knowledge about MCD suggests mTOR inhibitors may have expanded utility in treatment-resistant epilepsy, while imaging techniques can better delineate the type and extent of these lesions. PMID:33099181 | DOI:10.1016/j.conb.2020.10.005

October 25, 2020

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