Mutations in NLRP5 are associated with reproductive wastage and multilocus imprinting disorders in humans.
Human-imprinting disorders are congenital disorders of growth, development and metabolism, associated with disturbance of parent of origin-specific DNA methylation at imprinted loci across the genome. Some imprinting disorders have higher than expected prevalence of monozygotic twinning, of assisted reproductive technology among parents, and of disturbance of multiple imprinted loci, for which few causative trans-acting mutations have been found. Here we report mutations in NLRP5 in five mothers of individuals affected by multilocus imprinting disturbance. Maternal-effect mutations of other human NLRP genes, NLRP7 and NLRP2, cause familial biparental hydatidiform mole and multilocus imprinting disturbance, respectively. Offspring of mothers with NLRP5 mutations have heterogenous clinical and epigenetic features, but cases include a discordant monozygotic twin pair, individuals with idiopathic developmental delay and autism, and families affected by infertility and reproductive wastage. NLRP5 mutations suggest connections between maternal reproductive fitness, early zygotic development and genomic imprinting.
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
Louise E
LE
Docherty
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
Faisal I
FI
Rezwan
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
Rebecca L
RL
Poole
Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter EX1 2ED, UK.
Claire L S
CL
Turner
Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter EX1 2ED, UK.
Emma
E
Kivuva
Department of Medical Genetics, University of Cambridge, and Cambridge NIHR Biomedical Research Centre, Addenbrooke's Hospital, Cambridge CP2 0QQ, UK.
Eamonn R
ER
Maher
Department of Clinical Genetics, University Hospitals Bristol, Bristol BS2 8EG, UK.
Sarah F
SF
Smithson
School of Clinical Sciences, University of Bristol, Bristol BS2 8AE, UK.
Julian P
JP
Hamilton-Shield
Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University, 71-252, Szczecin, Poland.
Michal
M
Patalan
Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University, 71-252, Szczecin, Poland.
Maria
M
Gizewska
Department of Paediatric Oncology, Pomeranian Medical University, 71-252 Szczecin, Poland.
Jaroslaw
J
Peregud-Pogorzelski
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
Jasmin
J
Beygo
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
Karin
K
Buiting
Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstr 55, 45122 Essen, Germany.
Bernhard
B
Horsthemke
Institut für Humangenetik, University Hospital, RWTH Aachen, Pauwelsstr 30, 52074 Aachen, Germany.
Lukas
L
Soellner
Institut für Humangenetik, University Hospital, RWTH Aachen, Pauwelsstr 30, 52074 Aachen, Germany.
Matthias
M
Begemann
Institut für Humangenetik, University Hospital, RWTH Aachen, Pauwelsstr 30, 52074 Aachen, Germany.
Thomas
T
Eggermann
Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
Emma
E
Baple
St George's Healthcare NHS Trust, University of London, London, SW17 0QT UK.
Sahar
S
Mansour
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.|Wessex Clinical Genetics Service, University Hospital Southampton NHS Foundation Trust, Southampton SO16 5YA, UK.
I Karen
IK
Temple
Academic Unit of Human Development and Health, Faculty of Medicine, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK.|Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK.
Deborah J G
http://orcid.org/0000-0003-3088-4401
DJ
Mackay
D000022:Abortion, Spontaneous / Q000235:genetics; D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000235:genetics; D001324:Autoantigens / Q000235:genetics*; D001506:Beckwith-Wiedemann Syndrome / Q000235:genetics*; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D003920:Diabetes Mellitus / Q000235:genetics*; D044127:Epigenesis, Genetic; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D006828:Hydatidiform Mole / Q000235:genetics; D007232:Infant, Newborn, Diseases / Q000235:genetics*; D007247:Infertility, Female / Q000235:genetics; D008297:Male; D024101:Mitochondrial Proteins; D009035:Mothers; D009154:Mutation; D009687:Nuclear Proteins; D009765:Obesity / Q000235:genetics; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D017422:Sequence Analysis, DNA; D056730:Silver-Russell Syndrome / Q000235:genetics*; D014430:Twins, Monozygotic; D014594:Uterine Neoplasms / Q000235:genetics; D055815:Young Adult
D001324:Autoantigens; D024101:Mitochondrial Proteins; C527221:NLRP5 protein, human; D009687:Nuclear Proteins