Trans-acting genetic variants causing multilocus imprinting disturbance (MLID): common mechanisms and consequences
Clinical Epigenetics, vol. 14, pp. 41
Abstract
BACKGROUND: Imprinting disorders are a group of congenital diseases which are characterized by molecular alterations affecting differentially methylated regions (DMRs). To date, at least twelve imprinting disorders have been defined with overlapping but variable clinical features including growth and metabolic disturbances, cognitive dysfunction, abdominal wall defects and asymmetry. In general, a single specific DMR is affected in an individual with a given imprinting disorder, but there are a growing number of reports on individuals with so-called multilocus imprinting disturbances (MLID), where aberrant imprinting marks (most commonly loss of methylation) occur at multiple DMRs. However, as the literature is fragmented, we reviewed the molecular and clinical data of 55 previously reported or newly identified MLID families with putative pathogenic variants in maternal effect genes (NLRP2, NLRP5, NLRP7, KHDC3L, OOEP, PADI6) and in other candidate genes (ZFP57, ARID4A, ZAR1, UHRF1, ZNF445). RESULTS: In 55 families, a total of 68 different candidate pathogenic variants were identified (7 in NLRP2, 16 in NLRP5, 7 in NLRP7, 17 in PADI6, 15 in ZFP57, and a single variant in each of the genes ARID4A, ZAR1, OOEP, UHRF1, KHDC3L and ZNF445). Clinical diagnoses of affected offspring included Beckwith-Wiedemann syndrome spectrum, Silver-Russell syndrome spectrum, transient neonatal diabetes mellitus, or they were suspected for an imprinting disorder (undiagnosed). Some families had recurrent pregnancy loss. CONCLUSIONS: Genomic maternal effect and foetal variants causing MLID allow insights into the mechanisms behind the imprinting cycle of life, and the spatial and temporal function of the different factors involved in oocyte maturation and early development. Further basic research together with identification of new MLID families will enable a better understanding of the link between the different reproductive issues such as recurrent miscarriages and preeclampsia in maternal effect variant carriers/families and aneuploidy and the MLID observed in the offsprings. The current knowledge can already be employed in reproductive and genetic counselling in specific situations.
Authors 19
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. teggermann@ukaachen.de
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Laboratory for Genome Diagnostics, Amsterdam UMC, Amsterdam, Netherlands
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Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain
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Affiliation as printed
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy
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IRCCS Istituto Auxologico Italiano
Affiliation as printed
Research Laboratory of Medical Cytogenetics and Molecular Genetics, Istituto Auxologico Italiano, IRCCS, Milan, Italy
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Hospital Txagorritxu · Hospital Universitario Araba
Affiliation as printed
Molecular (Epi)Genetics Laboratory, Bioaraba Health Research Institute, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Alava, Spain
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Amsterdam University Medical Centers
Affiliation as printed
Department of Human Genetics, Laboratory for Genome Diagnostics, Amsterdam UMC, Amsterdam, Netherlands
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University Hospital Southampton NHS Foundation Trust
Affiliation as printed
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
Wessex Clinical Genetics Service, University Hospital Southampton, Southampton, UK
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University Hospital Southampton NHS Foundation Trust
Affiliation as printed
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton, UK
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University of Campania "Luigi Vanvitelli" · Institute of Genetics and Biophysics
Affiliation as printed
Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania 'Luigi Vanvitelli', Caserta, Italy
Institute of Genetics and Biophysics 'Adriano Buzzati-Traverso' CNR, Naples, Italy
Institute of Genetics and Biophysics 'Adriano Buzzati–Traverso' CNR, Naples, Italy
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National Center For Child Health and Development
Affiliation as printed
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Ohkura, Setagayaku, Tokyo, Japan
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Hamamatsu University School of Medicine · Hamamatsu Medical Center
Affiliation as printed
Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan
Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan
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Hospital Universitario La Paz · Instituto de Salud Carlos III · Centre for Biomedical Network Research on Rare Diseases · ERN ITHACA
Affiliation as printed
CIBERER-ISCIII and INGEMM, Institute of Medical and Molecular Genetics, Hospital Universitario La Paz, Madrid, Spain
ERN-Ithaca, European Reference Networks, Madrid, Spain
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Affiliation as printed
School of Biological Sciences, University of East Anglia, Norwich, UK
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University of Cambridge · Cambridge University Hospitals NHS Foundation Trust
Affiliation as printed
Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
Department of Medical Genetics, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ, UK
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University of Copenhagen · Copenhagen University Hospital · Rigshospitalet · Kennedy Center
Affiliation as printed
Department of Clinical Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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