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

doi:10.1002/humu.22837

Case Reports

. 2015 Oct;36(10):1009-1014.

doi: 10.1002/humu.22837. Epub 2015 Aug 6.

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

P Y Billie Au^#¹, Jing You^#^{2

3}, Oana Caluseriu⁴, Jeremy Schwartzentruber⁵, Jacek Majewski⁵, Francois P Bernier^{1

6}, Marcia Ferguson⁷; Care for Rare Canada Consortium; David Valle^{3

8

9}, Jillian S Parboosingh^{1

6}, Nara Sobreira³, A Micheil Innes^#^{1

6}, Antonie D Kline^#⁷

Affiliations

¹ Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.
² Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Human Genetics, McGill and Genome Quebec Innovation Center, McGill University, Quebec, Canada.
⁶ Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
⁷ Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.
⁸ Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
⁹ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

^# Contributed equally.

PMID: 26173930
PMCID: PMC4589226
DOI: 10.1002/humu.22837

Case Reports

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

P Y Billie Au et al. Hum Mutat. 2015 Oct.

. 2015 Oct;36(10):1009-1014.

doi: 10.1002/humu.22837. Epub 2015 Aug 6.

Authors

Affiliations

¹ Department of Medical Genetics, University of Calgary, Cumming School of Medicine, Alberta, Canada.
² Predoctoral Training Program in Human Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
³ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴ Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
⁵ Department of Human Genetics, McGill and Genome Quebec Innovation Center, McGill University, Quebec, Canada.
⁶ Alberta Children's Hospital, Research Institute for Child and Maternal Health, University of Calgary, Alberta, Canada.
⁷ Harvey Institute for Human Genetics, Department of Pediatrics, Greater Baltimore Medical Center, Baltimore, MD.
⁸ Center for Inherited Disease Research, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA.
⁹ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

^# Contributed equally.

PMID: 26173930
PMCID: PMC4589226
DOI: 10.1002/humu.22837

Abstract

We report a new syndrome due to loss-of-function variants in the heterogeneous nuclear ribonucleoprotein K gene (HNRNPK). We describe two probands: one with a de novo frameshift (NM_002140.3: c.953+1dup), and the other with a de novo splice donor site variant (NM_002140.3: c.257G>A). Both probands have intellectual disability, a shared unique craniofacial phenotype, and connective tissue and skeletal abnormalities. The identification of this syndrome was made possible by a new online tool, GeneMatcher, which facilitates connections between clinicians and researchers based on shared interest in candidate genes. This report demonstrates that new Web-based approaches can be effective in helping investigators solve exome sequencing projects, and also highlights the newer paradigm of "reverse phenotyping," where characterization of syndromic features follows the identification of genetic variants.

Keywords: GeneMatcher; HNRNPK; WES; matchmaker exchange; reverse phenotyping.

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Figures

**Figure 1. Clinical features of probands with HNRNPK loss of function variants**
Proband 1 (A-G) and Proband 2 (H-K). A) Proband 1 at 13 years. B) Hands of proband 1, with fifth finger clinodactyly, prominent joints and shorter distal phalanges. C) High palate and bifid uvula in proband 1. D) T2 coronal MRI of proband 1 at age 12, demonstrating multiple vertebral segmentation defects and thoracolumbar scoliosis. H) Proband 2 at 11 years. E and I) Bifid tongues with prominent midline groove in proband 2 (I), and prominent midline groove of tongue in proband 1 (E). F and G) Proband 1 at ages 14 months and 8 years. J and K) Proband 2 at 1 year and 8 years. L) Individual described by Hancarova et al. (2015) at age 6 years. M) Representative western blot demonstrating reduced hn RNPK protein expression in proband 2 fibroblasts (P2) versus control fibroblasts (C1-3). N) Comparison of mean hn RNPK protein expression levels determined from 3 independent western blots, p = 0.008426. Republished with permission.

See this image and copyright information in PMC

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References

1. Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. - PMC - PubMed
1. Au PY, Racher HE, Graham JM, Jr., Kramer N, Lowry RB, Parboosingh JS, Innes AM. De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review. Am J Med Genet A. 2014;164A:676–684. - PubMed
1. Barboro P, Ferrari N, Balbi C. Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression. Cancer Lett. 2014;352:152–159. - PubMed
1. Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925–933. - PMC - PubMed
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[1] Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. - PMC - PubMed

[2] Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491:56–65. - PMC - PubMed

[3] Au PY, Racher HE, Graham JM, Jr., Kramer N, Lowry RB, Parboosingh JS, Innes AM. De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review. Am J Med Genet A. 2014;164A:676–684. - PubMed

[4] Au PY, Racher HE, Graham JM, Jr., Kramer N, Lowry RB, Parboosingh JS, Innes AM. De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and a clinical review. Am J Med Genet A. 2014;164A:676–684. - PubMed

[5] Barboro P, Ferrari N, Balbi C. Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression. Cancer Lett. 2014;352:152–159. - PubMed

[6] Barboro P, Ferrari N, Balbi C. Emerging roles of heterogeneous nuclear ribonucleoprotein K (hnRNP K) in cancer progression. Cancer Lett. 2014;352:152–159. - PubMed

[7] Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925–933. - PMC - PubMed

[8] Bernier FP, Caluseriu O, Ng S, Schwartzentruber J, Buckingham KJ, Innes AM, Jabs EW, Innis JW, Schuette JL, Gorski JL, Byers PH, Andelfinger G, et al. Haploinsufficiency of SF3B4, a component of the pre-mRNA spliceosomal complex, causes Nager syndrome. Am J Hum Genet. 2012;90:925–933. - PMC - PubMed

[9] Bomsztyk K, Denisenko O, Ostrowski J. hnRNP K: one protein multiple processes. Bioessays. 2004;26:629–638. - PubMed

[10] Bomsztyk K, Denisenko O, Ostrowski J. hnRNP K: one protein multiple processes. Bioessays. 2004;26:629–638. - PubMed

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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

Affiliations

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

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