University of Oulu

Choufani, S., McNiven, V., Cytrynbaum, C., Jangjoo, M., Adam, M. P., Bjornsson, H. T., Harris, J., Dyment, D. A., Graham, G. E., Nezarati, M. M., Aul, R. B., Castiglioni, C., Breckpot, J., Devriendt, K., Stewart, H., Banos-Pinero, B., Mehta, S., Sandford, R., Dunn, C., … Weksberg, R. (2022). An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. The American Journal of Human Genetics, 109(10), 1867–1884.

An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome

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Author: Choufani, Sanaa1; McNiven, Vanda2,3,4; Cytrynbaum, Cheryl1,2;
Organizations: 1Hosp Sick Children, Res Inst, Genet & Genome Biol Program, Toronto, ON M5G IX8, Canada.
2Univ Toronto, Hosp Sick Children, Div Clin & Metab Genet, Dept Pediat, Toronto, ON M5G IX8, Canada.
3Univ Hlth Network, Fred A Litwin Family Ctr Genet Med, Toronto, ON M5T 3L9, Canada.
4Mt Sinai Hosp, Toronto, ON M5T 3L9, Canada.
5Univ Washington, Div Med Genet, Dept Pediat, Seattle, WA 98105 USA.
6Johns Hopkins Univ, Sch Med, McKusickNathans Inst Genet Med, Dept Med Genet, Baltimore, MD 21205 USA.
7Univ Iceland, Fac Med, IS-101 Reykjavik, Iceland.
8Kennedy Krieger Inst, Baltimore, MD 21205 USA.
9Univ Ottawa, Childrens Hosp Eastern Ontario Res Inst, Ottawa, ON K1H 5B2, Canada.
10Univ Ottawa, Childrens Hosp Eastern Ontario, Div Genet, Ottawa, ON K1H 8L1, Canada.
11North York Gen Hosp, Genet Program, Toronto, ON M2K IE1, Canada.
12Mackenzie Hlth, Richmond Hill, ON L4C 4Z3, Canada.
13Clin Las Condes, Dept Neurol Pediatr, Santiago 7591046, Chile.
14Univ Hosp Leuven, Ctr Human Genet, B-3000 Leuven, Belgium.
15Oxford Univ Hosp, NHS Fdn Trust, Oxford Ctr Genom Med, Nuffield Orthopaed Ctr, Oxford OX3 7HE, England.
16Oxford Univ Hosp NHS Fdn Trust, Oxford Reg Genet Labs, Oxford OX3 7LE, England.
17Adden brookes Hosp, Dept Clin Genet, Cambridge CB2 0QQ, England.
18Univ Bourgogne Franche Comte, CHU Besancon, Ctr Genet, F-25000 Besancon, France.
19Univ Bourgogne, Federat Hosp, Univ Med Translationnelle & Anomalies, CHU Dijon Bourgogne,Inserm UMR1231 GAD, F-21079 Dijon, France.
20Ctr Hosp Univ Dijon Bourgogne, UF Diagnost Genom & Malad & FHU TRANSLAD, F-21079 Dijon, France.
21Ctr Hosp Univ Dijon Bourgogne, Ctr Reference Anomal Dev & Syndromes Malformat, F-21079 Dijon, France.
22Inst Pathol & Genet, Dept Genet Clin, B-6041 Gosselies, Belgium.
23Univ Europea Madrid, Sch Med, Hosp Univ Quironsalud, Dept Pediat & Neurol, Madrid 28224, Spain.
24NIMGenetics, Genon & Med, Madrid 28108, Spain.
25King Faisal Specialist Hosp & Res Ctr, Dept Translat Gen, Ctr Genom Med, Riyadh 11211, Saudi Arabia.
26King Abdulaziz City Sci & Technol, Ctr Excellence Biomed, Riyadh 12354, Saudi Arabia.
27Hamad Med Corp, Dept Adult & Pediat Med Genet, Doha 3050, Qatar.
28Sidra Med, Div Genet & Genom Med, Doha 26999, Qatar.
29Duke Univ, Dept Pediat Med Genet, Durham, NC 27710 USA.
30Cedars Sinai Med Ctr, Dept Pediat, Med Genet, Los Angeles, CA 90048 USA.
31Harvard Med Sch, Boston Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA.
32NYU Grossman Sch Med, Ctr Human Genet Genom & Dept Pediat, New York, NY 10016 USA.
33Med Res Ctr, PEDEGO Res Unit, Oulu, Finland.
34Univ Oulu, Dept Clin Genet, Oulu, Finland.
35Oulu Univ Hosp, Oulu 90220, Finland.
36Univ Newcastle, Newcastle 2308, Australia.
37BC Childrens Hosp, Dept Pediat, Fac Med, Vancouver, BC, Canada.
38Univ British Columbia, Vancouver, BC V6H 3N1, Canada.
39Univ Hosp Southampton NHS Fdn Trust, Wessex Clin Genet Serv, Southampton, England.
40Univ Southampton, Human Dev & Hlth, Fac Med, Southampton, England.
41Dalhousie Univ, Div Med Genet, Dept Pediat, Halifax, NS B3K 6R8, Canada.
42Kaiser Permanente Oakland, Dept Med Genet, 3505 Broadway, Oakland, CA 94611 USA.
43Hosp Gen Univ Alicante Dr Balmis, Pediatrician Dept, Pintor Baeza 11, Alicante 03010, Spain.
44Hosp Gen Univ Alicante Dr Balmis, Internal Med Dept, Inst Hlth & Biomed Res Alicante, Pintor Baeza 11, Alicante 03010, Spain.
45CIBERER, Madrid 28042, Spain.
46Univ Hosp Paz, Inst Med & Mol Genet, INGEMM Idipaz, Madrid 28046, Spain.
47European Reference Network, ITHACA, B-1000 Brussels, Belgium.
48La Paz Univ Hosp, Neuropediat Serv, Madrid 28046, Spain.
49Univ Hosp Geneva, Dept Med Genet, CH-1205 Geneva, Switzerland.
50Univ Calgary, Alberta Childrens Hosp Res Inst Child & Maternal, Dept Med Genet, Cumming Sch Med, Calgary, AB T2N 4N1, Canada.
51Greater Baltimore Med Ctr, Harvey Inst Human Genet, Baltimore, MD 21204 USA.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 2.2 MB)
Persistent link:
Language: English
Published: Elsevier, 2022
Publish Date: 2022-12-15


Au-Kline syndrome (AKS) is a neurodevelopmental disorder associated with multiple malformations and a characteristic facial gestalt. The first individuals ascertained carried de novo loss-of-function (LoF) variants in HNRNPK. Here, we report 32 individuals with AKS (26 previously unpublished), including 13 with de novo missense variants. We propose new clinical diagnostic criteria for AKS that differentiate it from the clinically overlapping Kabuki syndrome and describe a significant phenotypic expansion to include individuals with missense variants who present with subtle facial features and few or no malformations. Many gene-specific DNA methylation (DNAm) signatures have been identified for neurodevelopmental syndromes. Because HNRNPK has roles in chromatin and epigenetic regulation, we hypothesized that pathogenic variants in HNRNPK may be associated with a specific DNAm signature. Here, we report a unique DNAm signature for AKS due to LoF HNRNPK variants, distinct from controls and Kabuki syndrome. This DNAm signature is also identified in some individuals with de novo HNRNPK missense variants, confirming their pathogenicity and the phenotypic expansion of AKS to include more subtle phenotypes. Furthermore, we report that some individuals with missense variants have an “intermediate” DNAm signature that parallels their milder clinical presentation, suggesting the presence of an epi-genotype phenotype correlation. In summary, the AKS DNAm signature may help elucidate the underlying pathophysiology of AKS. This DNAm signature also effectively supported clinical syndrome delineation and is a valuable aid for variant interpretation in individuals where a clinical diagnosis of AKS is unclear, particularly for mild presentations.

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Series: American journal of human genetics
ISSN: 0002-9297
ISSN-E: 1537-6605
ISSN-L: 0002-9297
Volume: 109
Issue: 10
Pages: 1867 - 1884
DOI: 10.1016/j.ajhg.2022.08.014
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: This work was supported by a Canadian Institutes of Health Research [IDS11-02]) grants to R.W. This work was also supported by a grant from SFARI (887172 for R.W.). F.A., H.A., and Z.R. acknowledge the King Salman Center for Disability Research for funding this work through Research Group no. RG-2022-010. J.T.-C., J.N., and P.L. were funded through FEDER funds PI20/01053. The work of G.E. was supported by the Jacob Goldfield Foundation and the RTW Charitable Foundation. P.Y.B.A. acknowledges the Rare Disease Foundation, which provided funding for AKS phenotype studies, and the Care4Rare Consortium, which supported the initial gene discovery. See supplemental information for detailed acknowledgment statements regarding the DDD study, the 100,000 Genomes Project, UDN, and the NIH Common Fund.
Copyright information: © 2022 The Authors. This is an open access article under the CC BY-NC-ND license (