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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Boycott, K. M. et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am. J. Hum. Genet. 100, 695–705, https://doi.org/10.1016/j.ajhg.2017.04.003 (2017). PubMed DOI PMC

Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696–704, https://doi.org/10.1038/gim.2015.148 (2016). PubMed DOI

Trujillano, D. et al. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur. J. Hum. Genet. 25, 176–182, https://doi.org/10.1038/ejhg.2016.146 (2017). PubMed DOI PMC

Dillon, O. J. et al. Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders. Eur. J. Hum. Genet. 26, 644–651, https://doi.org/10.1038/s41431-018-0099-1 (2018). PubMed DOI PMC

Sobreira, N. L. M. et al. Matchmaker Exchange. Curr. Protoc. Hum. Genet. 95, 9.31.1–9.31.15, https://doi.org/10.1002/cphg.50 (2017). DOI

Au, P. Y. B. et al. GeneMatcher aids in the identification of a new malformation syndrome with intellectual disability, unique facial dysmorphisms, and skeletal and connective tissue abnormalities caused by de novo variants in HNRNPK. Hum. Mutat. 36, 1009–1014, https://doi.org/10.1002/humu.22837 (2015). PubMed DOI PMC

O’Donnell-Luria, A. H. et al. Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy. Am. J. Hum. Genet. 104, 1210–1222, https://doi.org/10.1016/j.ajhg.2019.03.021 (2019). PubMed DOI PMC

Bruel, A.-L. et al. 2.5 years’ experience of GeneMatcher data-sharing: a powerful tool for identifying new genes responsible for rare diseases. Genet. Med. 21, 1657–1661, https://doi.org/10.1038/s41436-018-0383-z (2019). PubMed DOI

Leduc, M. S. et al. De novo apparent loss-of-function mutations in PRR12 in three patients with intellectual disability and iris abnormalities. Hum. Genet. 137, 257–264, https://doi.org/10.1007/s00439-018-1877-0 (2018). PubMed DOI

Córdova-Fletes, C. et al. A de novo t(10;19)(q22.3;q13.33) leads to ZMIZ1/PRR12 reciprocal fusion transcripts in a girl with intellectual disability and neuropsychiatric alterations. Neurogenetics. 16, 287–298, https://doi.org/10.1007/s10048-015-0452-2 (2015). PubMed DOI

Miller, J. A. et al. Transcriptional landscape of the prenatal human brain. Nature. 508, 199–206, https://doi.org/10.1038/nature13185 (2014). PubMed DOI PMC

Bult, C. J., Blake, J. A., Smith, C. L., Kadin, J. A., Richardson, J. E. & Mouse Genome Database Group. Mouse Genome Database (MGD) 2019. Nucleic Acids Res. 47, D801–D806, https://doi.org/10.1093/nar/gky1056 (2019).

Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443, https://doi.org/10.1038/s41586-020-2308-7 (2020). PubMed DOI PMC

Sobreira, N., Schiettecatte, F., Valle, D. & Hamosh, A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36, 1928–1930, https://doi.org/10.1002/humu.22844 (2015). DOI

Gu, S. et al. Mechanisms for complex chromosomal insertions. PLoS Genet. 12, e1006446, https://doi.org/10.1371/journal.pgen.1006446 (2016). PubMed DOI PMC

Tapial, J. et al. An atlas of alternative splicing profiles and functional associations reveals new regulatory programs and genes that simultaneously express multiple major isoforms. Genome Res. 27, 1759–1768, https://doi.org/10.1101/gr.220962.117 (2017). PubMed DOI PMC

Firth, H. V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533, https://doi.org/10.1016/j.ajhg.2009.03.010 (2009). PubMed DOI PMC

Mirzaa, G. et al. PIK3CA-associated developmental disorders exhibit distinct classes of mutations with variable expression and tissue distribution. JCI Insight. 1, e87623 (2016).

Stolerman, E. S. et al. Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features. Am. J. Med. Genet. A. 179, 1276–1286, https://doi.org/10.1002/ajmg.a.61173 (2019). PubMed DOI

Unlu, G. et al. GRIK5 genetically regulated expression associated with eye and vascular phenomes: discovery through iteration among biobanks, electronic health records, and zebrafish. Am. J. Hum. Genet. 104, 503–519, https://doi.org/10.1016/j.ajhg.2019.01.017 (2019). PubMed DOI PMC

Reis, L. M. et al. Dominant variants in PRR12 result in unilateral or bilateral complex microphthalmia. Clin. Genet. https://doi.org/10.1111/cge.13897 (2020).

Fishilevich, S. et al. GeneHancer: genome-wide integration of enhancers and target genes in GeneCards. Database (Oxford). 2017, bax028 (2017).

Zerbino, D. R. et al. Ensembl 2018. Nucleic Acids Res. 46, D754–D761, https://doi.org/10.1093/nar/gkx1098 (2018). PubMed DOI

Bernstein, B. E. et al. A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell. 125, 315–326, https://doi.org/10.1016/j.cell.2006.02.041 (2006). PubMed DOI

Harikumar, A. & Meshorer, E. Chromatin remodeling and bivalent histone modifications in embryonic stem cells. EMBO Rep. 16, 1609–1619, https://doi.org/10.15252/embr.201541011 (2015). PubMed DOI PMC

Nagase, T. et al. Prediction of the coding sequences of unidentified human genes. XV. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 6, 337–345, https://doi.org/10.1093/dnares/6.5.337 (1999). PubMed DOI

Havugimana, P. C. et al. A census of human soluble protein complexes. Cell. 150, 1068–1081, https://doi.org/10.1016/j.cell.2012.08.011 (2012). PubMed DOI PMC

Kim, B. R. et al. Identification of the SOX2 interactome by BioID reveals EP300 as a mediator of SOX2-dependent squamous differentiation and lung squamous cell carcinoma growth. Mol. Cell. Proteomics. 16, 1864–1888, https://doi.org/10.1074/mcp.M116.064451 (2017). PubMed DOI PMC

Giurato, G. et al. Quantitative mapping of RNA-mediated nuclear estrogen receptor β interactome in human breast cancer cells. Sci Data. 5, 180031, https://doi.org/10.1038/sdata.2018.31 (2018). PubMed DOI PMC

Fountain, M. D. et al. Pathogenic variants in USP7 cause a neurodevelopmental disorder with speech delays, altered behavior, and neurologic anomalies. Genet. Med. 21, 1797–1807 (2019).

Ragge, N. K. et al. SOX2 anophthalmia syndrome. Am. J. Med. Genet. A. 135, 1–7, https://doi.org/10.1002/ajmg.a.30642 (2005). discussion 8. PubMed DOI

Baetens, D. et al. Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development. Genet. Med. 20, 717–727, https://doi.org/10.1038/gim.2017.163 (2018). PubMed DOI

Balci, T. B. et al. Debunking Occam’s razor: diagnosing multiple genetic diseases in families by whole-exome sequencing. Clin. Genet. 92, 281–289, https://doi.org/10.1111/cge.12987 (2017). PubMed DOI

Posey, J. E. et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N. Engl. J. Med. 376, 21–31, https://doi.org/10.1056/NEJMoa1516767 (2017). PubMed DOI

de Geus, C. M. et al. Guidelines in CHARGE syndrome and the missing link: cranial imaging. Am. J. Med. Genet. C Semin. Med. Genet. 175, 450–464, https://doi.org/10.1002/ajmg.c.31593 (2017). PubMed DOI PMC

Andreou, A. M. et al. TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation, and transcriptional repression. Am. J. Hum. Genet. 81, 700–712, https://doi.org/10.1086/521033 (2007). PubMed DOI PMC

Al-Baradie, R. et al. Duane radial ray syndrome (Okihiro syndrome) maps to 20q13 and results from mutations in SALL4, a new member of the SAL family. Am. J. Hum. Genet. 71, 1195–1199, https://doi.org/10.1086/343821 (2002). PubMed DOI PMC

Obayashi, T., Kagaya, Y., Aoki, Y., Tadaka, S. & Kinoshita, K. COXPRESdb v7: a gene coexpression database for 11 animal species supported by 23 coexpression platforms for technical evaluation and evolutionary inference. Nucleic Acids Res. 47, D55–D62, https://doi.org/10.1093/nar/gky1155 (2019). PubMed DOI

Jiao, X. et al. DAVID-WS: a stateful web service to facilitate gene/protein list analysis. Bioinformatics. 28, 1805–1806, https://doi.org/10.1093/bioinformatics/bts251 (2012). PubMed DOI PMC

Choudhary, C. et al. Lysine acetylation targets protein complexes and co-regulates major cellular functions. Science. 325, 834–840, https://doi.org/10.1126/science.1175371 (2009). PubMed DOI

Paralogous Genes Involved in Embryonic Development: Lessons from the Eye and Other Tissues