The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Pellikaan, Karlijn; van Woerden, Geeske M.; Kleinendorst, Lotte; Rosenberg, Anna G. W.; Horsthemke, Bernhard; Grosser, Christian; van Zutven, Laura J. C. M.; van Rossum, Elisabeth F. C.; van der Lely, Aart J.; Resnick, James L.; Brüggenwirth, Hennie T.; van Haelst, Mieke M.; de Graaff, Laura C. G.

doi:10.3390/genes12060875

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The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

Karlijn Pellikaan

^1,2

Geeske M. van Woerden

^3,4,5,

⁶,

^1,2,

⁷,

^7,8,

Laura J. C. M. van Zutven

⁵,

Elisabeth F. C. van Rossum

^1,9,

Aart J. van der Lely

James L. Resnick

¹⁰,

Hennie T. Brüggenwirth

⁵,

Mieke M. van Haelst

⁶ and

Laura C. G. de Graaff

^1,2,4,11,*

Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Centre Rotterdam, 3015 GD Rotterdam, The Netherlands

Dutch Centre of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands

Department of Neuroscience, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands

⁴

The ENCORE Expertise Centre for Neurodevelopmental Disorders, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands

⁵

Department of Clinical Genetics, Erasmus University Medical Centre, 3015 GD Rotterdam, The Netherlands

⁶

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, 1081 HV Amsterdam, The Netherlands

⁷

Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, 45147 Essen, Germany

⁸

Praxis für Humangenetik Tübingen, 72076 Tuebingen, Germany

⁹

Obesity Center CGG, Erasmus MC, University Medical Centre Rotterdam, 3015 GD Rotterdam, The Netherlands

¹⁰

Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA

¹¹

Academic Centre for Growth Disorders, Erasmus MC Rotterdam, 3015 GD Rotterdam, The Netherlands

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Academic Editor: Mara Giordano

Genes 2021, 12(6), 875; https://doi.org/10.3390/genes12060875

Received: 30 April 2021 / Revised: 25 May 2021 / Accepted: 27 May 2021 / Published: 7 June 2021

(This article belongs to the Special Issue Novel Genetic causes of Pitutary Hormone Deficiency)

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Abstract

Prader–Willi syndrome (PWS) is a rare genetic condition characterized by hypotonia, intellectual disability, and hypothalamic dysfunction, causing pituitary hormone deficiencies and hyperphagia, ultimately leading to obesity. PWS is most often caused by the loss of expression of a cluster of genes on chromosome 15q11.2-13. Patients with Prader–Willi-like syndrome (PWLS) display features of the PWS phenotype without a classical PWS genetic defect. We describe a 46-year-old patient with PWLS, including hypotonia, intellectual disability, hyperphagia, and pituitary hormone deficiencies. Routine genetic tests for PWS were normal, but a homozygous missense variant NM_003097.3(SNRPN):c.193C>T, p.(Arg65Trp) was identified. Single nucleotide polymorphism array showed several large regions of homozygosity, caused by high-grade consanguinity between the parents. Our functional analysis, the ‘Pipeline for Rapid in silico, in vivo, in vitro Screening of Mutations’ (PRiSM) screen, showed that overexpression of SNRPN-p.Arg65Trp had a dominant negative effect, strongly suggesting pathogenicity. However, it could not be confirmed that the variant was responsible for the phenotype of the patient. In conclusion, we present a unique homozygous missense variant in SNURF-SNRPN in a patient with PWLS. We describe the diagnostic trajectory of this patient and the possible contributors to her phenotype in light of the current literature on the genotype–phenotype relationship in PWS.

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Keywords: prader–willi syndrome; genetic variation; genomic imprinting; genetics; brain

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MDPI and ACS Style

Pellikaan, K.; van Woerden, G.M.; Kleinendorst, L.; Rosenberg, A.G.W.; Horsthemke, B.; Grosser, C.; van Zutven, L.J.C.M.; van Rossum, E.F.C.; van der Lely, A.J.; Resnick, J.L.; Brüggenwirth, H.T.; van Haelst, M.M.; de Graaff, L.C.G. The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature. Genes 2021, 12, 875. https://doi.org/10.3390/genes12060875

AMA Style

Pellikaan K, van Woerden GM, Kleinendorst L, Rosenberg AGW, Horsthemke B, Grosser C, van Zutven LJCM, van Rossum EFC, van der Lely AJ, Resnick JL, Brüggenwirth HT, van Haelst MM, de Graaff LCG. The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature. Genes. 2021; 12(6):875. https://doi.org/10.3390/genes12060875

Chicago/Turabian Style

Pellikaan, Karlijn, Geeske M. van Woerden, Lotte Kleinendorst, Anna G. W. Rosenberg, Bernhard Horsthemke, Christian Grosser, Laura J. C. M. van Zutven, Elisabeth F. C. van Rossum, Aart J. van der Lely, James L. Resnick, Hennie T. Brüggenwirth, Mieke M. van Haelst, and Laura C. G. de Graaff. 2021. "The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature" Genes 12, no. 6: 875. https://doi.org/10.3390/genes12060875

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The Diagnostic Journey of a Patient with Prader–Willi-Like Syndrome and a Unique Homozygous SNURF-SNRPN Variant; Bio-Molecular Analysis and Review of the Literature

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