TY - JOUR
T1 - 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
AU - Pellikaan, Karlijn
AU - van Woerden, Geeske M.
AU - Kleinendorst, Lotte
AU - Rosenberg, Anna G. W.
AU - Horsthemke, Bernhard
AU - Grosser, Christian
AU - van Zutven, Laura J. C. M.
AU - van Rossum, Elisabeth F. C.
AU - van der Lely, Aart J.
AU - Resnick, James L.
AU - Brüggenwirth, Hennie T.
AU - van Haelst, Mieke M.
AU - de Graaff, Laura C. G.
N1 - Publisher Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
KW - Brain
KW - Genetic variation
KW - Genetics
KW - Genomic imprinting
KW - Prader–willi syndrome
UR - http://www.scopus.com/inward/record.url?scp=85108503100&partnerID=8YFLogxK
U2 - https://doi.org/10.3390/genes12060875
DO - https://doi.org/10.3390/genes12060875
M3 - Article
C2 - 34200226
SN - 2073-4425
VL - 12
JO - Genes
JF - Genes
IS - 6
M1 - 875
ER -