PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

Al Balqa Applied University Faculty of Medicine Al Salt Jordan

Baylor Genetics Laboratory Houston TX USA

Center for Medical Genetics Keio University School of Medicine Tokyo Japan

Children's Health Research Institute London ON Canada

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

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

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

Department of Biotechnology and Genetic Engineering Philadelphia University Amman Jordan

Department of Genetic Medicine Johns Hopkins Hospital Baltimore MD USA

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

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

Department of Medical Genetics Mercyhealth Javon Bea Hospital Rockford IL USA

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

Department of Medical Genetics University of Alberta Edmonton AB Canada

Department of Medical Sciences University of Torino Torino Italy

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

Department of Paediatrics Schulich School of Medicine and Dentistry Western University London ON Canada

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

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

Department of Pediatrics Gifu University Graduate School of Medicine Gifu Japan

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

Department of Pediatrics Regina Margherita Children Hospital Turin Italy

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

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

GeneDx Gaithersburg MD USA

Institute of Human Genetics Friedrich Alexander Universität Erlangen Nürnberg Erlangen Germany

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

Medical Genetics Program of Southwestern Ontario London Health Sciences Centre London ON Canada

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

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

Vanderbilt Genetics Institute Vanderbilt University Nashville TN USA

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$a Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities / $c F. Chowdhury, L. Wang, M. Al-Raqad, DJ. Amor, A. Baxová, Š. Bendová, E. Biamino, A. Brusco, O. Caluseriu, NJ. Cox, T. Froukh, M. Gunay-Aygun, M. Hančárová, D. Haynes, S. Heide, G. Hoganson, T. Kaname, B. Keren, K. Kosaki, K. Kubota, JM. Lemons, MA. Magriña, PR. Mark, MT. McDonald, S. Montgomery, GM. Morley, H. Ohnishi, N. Okamoto, D. Rodriguez-Buritica, P. Rump, Z. Sedláček, K. Schatz, H. Streff, T. Uehara, JS. Walia, PG. Wheeler, A. Wiesener, C. Zweier, K. Kawakami, IM. Wentzensen, SR. Lalani, VM. Siu, W. Bi, TB. Balci

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$a PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These findings support PRR12 haploinsufficiency as a cause for a novel disorder with a wide clinical spectrum marked chiefly by neurodevelopmental and eye abnormalities.

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