Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities.

Animals Haploinsufficiency / genetics Humans Intellectual Disability / genetics Mice Muscle Hypotonia Mutation, Missense Phenotype

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
07 2021
Historique:
received: 04 10 2020
accepted: 11 02 2021
revised: 11 02 2021
pubmed: 8 4 2021
medline: 13 8 2021
entrez: 7 4 2021
Statut: ppublish

Résumé

Proline Rich 12 (PRR12) is a gene of unknown function with suspected DNA-binding activity, expressed in developing mice and human brains. Predicted loss-of-function variants in this gene are extremely rare, indicating high intolerance of haploinsufficiency. Three individuals with intellectual disability and iris anomalies and truncating de novo PRR12 variants were described previously. We add 21 individuals with similar PRR12 variants identified via matchmaking platforms, bringing the total number to 24. We observed 12 frameshift, 6 nonsense, 1 splice-site, and 2 missense variants and one patient with a gross deletion involving PRR12. Three individuals had additional genetic findings, possibly confounding the phenotype. All patients had developmental impairment. Variable structural eye defects were observed in 12/24 individuals (50%) including anophthalmia, microphthalmia, colobomas, optic nerve and iris abnormalities. Additional common features included hypotonia (61%), heart defects (52%), growth failure (54%), and kidney anomalies (35%). PrediXcan analysis showed that phecodes most strongly associated with reduced predicted PRR12 expression were enriched for eye- (7/30) and kidney- (4/30) phenotypes, such as wet macular degeneration and chronic kidney disease. These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Identifiants

DOI: 10.1038/s41436-021-01129-6 PMID: 33824499
pubmed: 33824499
doi: 10.1038/s41436-021-01129-6
pii: S1098-3600(21)05035-8
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1234-1245

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Auteurs

Fuad Chowdhury (F)

Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.

Lei Wang (L)

Baylor Genetics Laboratory, Houston, TX, USA.

Mohammed Al-Raqad (M)

Al-Balqa Applied University, Faculty of Medicine, Al-Salt, Jordan.

David J Amor (DJ)

Murdoch Children's Research Institute and University of Melbourne Department of Paediatrics, Royal Children's Hospital, Parkville, Australia.

Alice Baxová (A)

Department of Biology and Medical Genetics, 1st Faculty of Medicine and University Hospital, Charles University, Prague, Czech Republic.

Šárka Bendová (Š)

Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic.

Elisa Biamino (E)

Department of Pediatrics, Regina Margherita Children Hospital, Turin, Italy.

Alfredo Brusco (A)

Department of Medical Sciences, University of Torino, Torino, Italy.

Oana Caluseriu (O)

Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada.

Nancy J Cox (NJ)

Vanderbilt Genetics Institute, Vanderbilt University, Nashville, TN, USA.

Tawfiq Froukh (T)

Department of Biotechnology and Genetic Engineering, Philadelphia University, Amman, Jordan.

Meral Gunay-Aygun (M)

Department of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.

Miroslava Hančárová (M)

Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic.

Devon Haynes (D)

Division of Genetics, Arnold Palmer Hospital for Children-Orlando Health, Orlando, FL, USA.

Solveig Heide (S)

Département de Génétique and CRMR « Déficience Intellectuelle », Hôpital de la Pitié Salpêtrière, APHP Sorbonne Université, Paris, France.

George Hoganson (G)

Department of Medical Genetics, Mercyhealth-Javon Bea Hospital, Rockford, IL, USA.

Tadashi Kaname (T)

Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan.

Boris Keren (B)

Département de Génétique and CRMR « Déficience Intellectuelle », Hôpital de la Pitié Salpêtrière, APHP Sorbonne Université, Paris, France.

Kenjiro Kosaki (K)

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Kazuo Kubota (K)

Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.

Jennifer M Lemons (JM)

Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Maria A Magriña (MA)

Medical Specialties Unit from City Hall São Jose dos Campos, São Paulo, Brazil.

Paul R Mark (PR)

Division of Medical Genetics and Genomics, Spectrum Health, Grand Rapids, MI, USA.

Marie T McDonald (MT)

Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.

Sarah Montgomery (S)

Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, NC, USA.

Gina M Morley (GM)

Department of Medical Genetics, Mercyhealth-Javon Bea Hospital, Rockford, IL, USA.

Hidenori Ohnishi (H)

Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan.

Nobuhiko Okamoto (N)

Department of Medical Genetics, Osaka Women's and Children's Hospital, Osaka, Japan.

David Rodriguez-Buritica (D)

Department of Pediatrics, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA.

Patrick Rump (P)

Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.

Zdeněk Sedláček (Z)

Department of Biology and Medical Genetics, 2nd Faculty of Medicine and University Hospital Motol, Charles University, Prague, Czech Republic.

Krista Schatz (K)

Department of Genetic Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.

Haley Streff (H)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Tomoko Uehara (T)

Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.

Jagdeep S Walia (JS)

Department of Pediatrics, Division of Medical Genetics, Kingston General Hospital, Kingston, ON, Canada.

Patricia G Wheeler (PG)

Division of Genetics, Arnold Palmer Hospital for Children-Orlando Health, Orlando, FL, USA.

Antje Wiesener (A)

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Christiane Zweier (C)

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Koichi Kawakami (K)

Laboratory of Molecular and Developmental Biology, National Institute of Genetics, Mishima, Japan.

Ingrid M Wentzensen (IM)

GeneDx, Gaithersburg, MD, USA.

Seema R Lalani (SR)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Victoria M Siu (VM)

Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.
Children's Health Research Institute, London, ON, Canada.

Weimin Bi (W)

Baylor Genetics Laboratory, Houston, TX, USA. wbi@bcm.edu.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA. wbi@bcm.edu.

Tugce B Balci (TB)

Department of Paediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. Tugce.Balci@lhsc.on.ca.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada. Tugce.Balci@lhsc.on.ca.
Children's Health Research Institute, London, ON, Canada. Tugce.Balci@lhsc.on.ca.
ORCID: 0000-0002-5409-8387

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Dosage génique › Haploinsuffisance › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Troubles mentaux › Troubles du développement neurologique › Déficience intellectuelle › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › États, signes et symptômes pathologiques › Signes et symptômes › Manifestations neurologiques › Manifestations neuromusculaires › Hypotonie musculaire › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › Haploinsufficiency of PRR12 causes a spectrum...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Haploinsufficiency of PRR12 causes a spectrum...