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



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.

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Fig. 1: Variant spectrum of PRR12 observed in this cohort.
Fig. 2: Facial features of some individuals with PRR12 variants.
Fig. 3: Subgrouping of the variable eye findings and comparison of phenotypes between variants that affect one or both isoforms.

Data availability

Any materials, data, and data sets produced from or used for this study will be made available upon request to the authors. The PRR12 variants reported by GeneDx have been submitted to ClinVar. SUB numbers with corresponding patient numbers are: Patient 1: SUB9233172; Patient 2: SUB9233619; Patient 6 SUB9246261; Patient 7: SUB9246275; Patient 9: SUB9246289; Patient 12: SUB9246294; Patient 14: SUB9246299; Patient 17: SUB9246311.


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We sincerely thank the patients and their families for their participation in this study. The authors thank the Genome Aggregation Database (gnomAD,, DECIPHER (, GTEx (, BrainSpan atlas (, GeneHancer (, and BioGRID (, which provided valuable open-source genomic, expression, and proteomic data. F.C. is supported by the Schulich Research Opportunities Program and Department of Paediatrics Summer Studentship from the Schulich School of Medicine and Dentistry, London, Ontario, Canada. Analysis of patient 13 was supported by funding appointed to Department of Medical Sciences from the Italian Ministry for Education, University and Research (Ministero dell’Istruzione, dell’Università e della Ricerca–MIUR) under the program “Dipartimenti di Eccellenza 2018–2022”; Project code D15D18000410001. ES was performed as part of the Autism Sequencing Consortium and was supported by the National Institute of Mental Health (MH111661). Special thanks to Evelise Riberi and Giovanni Battista Ferrero for their analysis in this patient. Analysis of patient 16 was supported by grants 17-29423A and LM2018132 from the Czech Ministries of Health and Education. Analyses for patients 4 and 5 were partly supported by Initiative on Rare and Undiagnosed Diseases in Pediatrics (IRUD-P) (16ek0109166h0002, 17ek0109151s1) (TK) from the Japanese Agency for Medical Research and Development (AMED) and JSPS KAKENHI Grant Number JP18K07863 (TK) from Japan Society for the Promotion of Science. Special thanks to Kumiko Yanagi for their assistance in the analysis of these patients. K. Kawakami is supported by grants J-RDMM JP19ek0109288 and JP20ek0109484 from AMED.

Author information




Conceptualization: T.B.B., W.B., V.M.S. Data curation: F.C., L.W., M.A.-R., D.J.A., A. Baxova, S.B., E.B., A. Brusco, O.C., T.F., M.G.-A., M.H., D.H., S.H., G.H., T.K., B.K., K. Kosaki, K. Kubota, J.M.L., M.A.M., P.R.M., M.T.M., S.M., G.M.M., H.O., N.O., D.R-B., P.R., Z.S., K.S., H.S., T.U., J.S.W., P.G.W., A.W., C.Z., I.M.W., S.R.L., V.M.S., T.B.B. Formal analysis: N.C., F.C. Funding acquisition: W.B., S.R.L., F.C., T.B.B, E.R., A.B., T.K., K. Kawakami. Investigation: N.C. Resources: T.B.B., I.M.W., W.B. Supervision: T.B.B. Visualization: F.C., L.W.; Writing—original draft: F.C. Writing—review & editing: M.A.-R., D.J.A., A. Brusco, M.G.-A., S.H., P.M., Z.S., W.B., T.B.B.

Corresponding authors

Correspondence to Weimin Bi or Tugce B. Balci.

Ethics declarations

Ethics declaration

Written informed consent was obtained from all patients in accordance with protocols approved by the appropriate human subject ethics committees: through Baylor College of Medicine for patients 7, 8, 12, 17, 18, 19, 21, 22, 23, and 24 and through their respective academic/health sciences center for the rest of the cohort. Consents for publication of photographs were attained from parents/legal guardians of patients 1, 3, 8, 10, 11, 12, 14, 16, 18, 19, 20, and 24. Detailed clinical information was submitted by each patient’s clinical genetics team via a clinical questionnaire. The complete set of clinical information is provided in Supplementary Table 1. This study was approved by the Institutional Review Board at Baylor College of Medicine.

Competing interests

W.B. and L.W. are employees of Baylor Miraca Genetics Laboratories, BMGL. I.M.W. is an employee of GeneDx, Inc. The other authors declare no competing interests.

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Chowdhury, F., Wang, L., Al-Raqad, M. et al. Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities. Genet Med (2021).

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