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

Abstract

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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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.

References

  1. 1.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    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).

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    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).

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    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).

    Article  Google Scholar 

  6. 6.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    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).

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    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).

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    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).

    Article  PubMed  Google Scholar 

  11. 11.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    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).

  13. 13.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    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).

    Article  Google Scholar 

  15. 15.

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

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

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

  19. 19.

    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).

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    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).

  22. 22.

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

  23. 23.

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

    CAS  Article  PubMed  Google Scholar 

  24. 24.

    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).

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    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).

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. 29.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    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).

  31. 31.

    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.

    Article  PubMed  Google Scholar 

  32. 32.

    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).

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    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).

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    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).

    CAS  Article  PubMed  Google Scholar 

  35. 35.

    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).

    Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 37.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 38.

    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).

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    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).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We sincerely thank the patients and their families for their participation in this study. The authors thank the Genome Aggregation Database (gnomAD, https://gnomad.broadinstitute.org/about), DECIPHER (http://decipher.sanger.ac.uk), GTEx (https://www.gtexportal.org/home/index.html), BrainSpan atlas (https://www.brainspan.org/), GeneHancer (http://www.genecards.org/), and BioGRID (https://thebiogrid.org/), 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.

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Authors

Contributions

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). https://doi.org/10.1038/s41436-021-01129-6

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