Title

Variant-specific effects define the phenotypic spectrum of HNRNPH2-associated neurodevelopmental disorders in males

Authors

Hans-Jürgen Kreienkamp, Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Matias Wagner, Institute of Human Genetics, Technical University of Munich, Munich, Germany.
Heike Weigand, Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Dr. von Hauner's Children's Hospital, University of Munich, Munich, Germany.
Allyn McConkie-Rossell, Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, USA.
Marie McDonald, Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, USA.
Boris Keren, Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Cyril Mignot, Département de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Julie Gauthier, Molecular Diagnostic Laboratory, CHU Sainte-Justine, Montreal, QC, Canada.
Jean-François Soucy, Molecular Diagnostic Laboratory, CHU Sainte-Justine, Montreal, QC, Canada.
Jacques L. Michaud, Molecular Diagnostic Laboratory, CHU Sainte-Justine, Montreal, QC, Canada.
Meghan Dumas, Division of Genetic, Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME, USA.
Rosemarie Smith, Division of Genetic, Department of Pediatrics, The Barbara Bush Children's Hospital, Maine Medical Center, Portland, ME, USA.
Ulrike Löbel, Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Maja Hempel, Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Christian Kubisch, Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
Jonas Denecke, Department of Pediatrics, University Medical Center Eppendorf, Hamburg, Germany.
Philippe M. Campeau, Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, Canada.
Jennifer M. Bain, Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, USA.
Davor Lessel, Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany. d.lessel@uke.de.

Document Type

Article

Publication Date

2-1-2022

Journal Title

Human genetics

MeSH Headings

Adolescent; Alternative Splicing (genetics); Amino Acid Substitution; Brain (diagnostic imaging); Child; Child, Preschool; Chromosomes, Human, X (genetics); Codon, Nonsense; Diseases in Twins (diagnostic imaging, genetics); Female; Frameshift Mutation; Genetic Association Studies; Genetic Variation; Heterogeneous-Nuclear Ribonucleoprotein Group F-H (genetics); Humans; Intellectual Disability (diagnostic imaging, genetics); Male; Mutation; Mutation, Missense; Neurodevelopmental Disorders (diagnostic imaging, genetics); Phenotype; RNA-Seq; Twins, Monozygotic; Young Adult

Abstract

Bain type of X-linked syndromic intellectual developmental disorder, caused by pathogenic missense variants in HRNRPH2, was initially described in six female individuals affected by moderate-to-severe neurodevelopmental delay. Although it was initially postulated that the condition would not be compatible with life in males, several affected male individuals harboring pathogenic variants in HNRNPH2 have since been documented. However, functional in-vitro analyses of identified variants have not been performed and, therefore, possible genotype-phenotype correlations remain elusive. Here, we present eight male individuals, including a pair of monozygotic twins, harboring pathogenic or likely pathogenic HNRNPH2 variants. Notably, we present the first individuals harboring nonsense or frameshift variants who, similarly to an individual harboring a de novo p.(Arg29Cys) variant within the first quasi-RNA-recognition motif (qRRM), displayed mild developmental delay, and developed mostly autistic features and/or psychiatric co-morbidities. Additionally, we present two individuals harboring a recurrent de novo p.(Arg114Trp), within the second qRRM, who had a severe neurodevelopmental delay with seizures. Functional characterization of the three most common HNRNPH2 missense variants revealed dysfunctional nucleocytoplasmic shuttling of proteins harboring the p.(Arg206Gln) and p.(Pro209Leu) variants, located within the nuclear localization signal, whereas proteins with p.(Arg114Trp) showed reduced interaction with members of the large assembly of splicing regulators (LASR). Moreover, RNA-sequencing of primary fibroblasts of the individual harboring the p.(Arg114Trp) revealed substantial alterations in the regulation of alternative splicing along with global transcriptome changes. Thus, we further expand the clinical and variant spectrum in HNRNPH2-associated disease in males and provide novel molecular insights suggesting the disorder to be a spliceopathy on the molecular level.

First Page

257

Last Page

272

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