Detailed Clinical and Psychological Phenotype of the X-linked HNRNPH2-Related Neurodevelopmental Disorder
Jennifer M Bain, Olivia Thornburg, Cheryl Pan, Donnielle Rome-Martin, Lia Boyle, Xiao Fan, Orrin Devinsky, Richard Frye, Silke Hamp, Cynthia G Keator, Nicole M LaMarca, Alexis B R Maddocks, Marcos Madruga-Garrido, Karen Y Niederhoffer, Francesca Novara, Angela Peron, Elizabeth Poole-Di Salvo, Rachel Salazar, Steven A Skinner, Gabriela Soares, Sylvie Goldman, Wendy K Chung, Jennifer M Bain, Olivia Thornburg, Cheryl Pan, Donnielle Rome-Martin, Lia Boyle, Xiao Fan, Orrin Devinsky, Richard Frye, Silke Hamp, Cynthia G Keator, Nicole M LaMarca, Alexis B R Maddocks, Marcos Madruga-Garrido, Karen Y Niederhoffer, Francesca Novara, Angela Peron, Elizabeth Poole-Di Salvo, Rachel Salazar, Steven A Skinner, Gabriela Soares, Sylvie Goldman, Wendy K Chung
Abstract
Objective: To expand the clinical phenotype of the X-linked HNRNPH2-related neurodevelopmental disorder in 33 individuals.
Methods: Participants were diagnosed with pathogenic or likely pathogenic variants in HNRNPH2 using American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria, largely identified via clinical exome sequencing. Genetic reports were reviewed. Clinical data were collected by retrospective chart review and caregiver report including standardized parent report measures.
Results: We expand our clinical characterization of HNRNPH2-related disorders to include 33 individuals, aged 2-38 years, both females and males, with 11 different de novo missense variants, most within the nuclear localization signal. The major features of the phenotype include developmental delay/intellectual disability, severe language impairment, motor problems, growth, and musculoskeletal disturbances. Minor features include dysmorphic features, epilepsy, neuropsychiatric diagnoses such as autism spectrum disorder, and cortical visual impairment. Although rare, we report early stroke and premature death with this condition.
Conclusions: The spectrum of X-linked HNRNPH2-related disorders continues to expand as the allelic spectrum and identification of affected males increases.
Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
Figures
References
- Hu WF, Chahrour MH, Walsh CA. The diverse genetic landscape of neurodevelopmental disorders. Annu Rev Genomics Hum Genet 2014;15:195–213.
- Jensen M, Girirajan S. Mapping a shared genetic basis for neurodevelopmental disorders. Genome Med 2017;9:109.
- Vorstman JAS, Parr JR, Moreno-De-Luca D, Anney RJL, Nurnberger JI Jr, Hallmayer JF. Autism genetics: opportunities and challenges for clinical translation. Nat Rev Genet 2017;18:362–376.
- Bassani S, Zapata J, Gerosa L, Moretto E, Murru L, Passafaro M. The neurobiology of X-linked intellectual disability. Neuroscientist 2013;19:541–552.
- des Portes V. X-linked mental deficiency. Handb Clin Neurol 2013;111:297–306.
- Marco EJ, Skuse DH. Autism-lessons from the X chromosome. Soc Cogn Affect Neurosci 2006;1:183–193.
- Somashekar PH, Narayanan DL, Jagadeesh S, et al. . Bain type of X‐linked syndromic mental retardation in a male with a pathogenic variant in HNRNPH2. Am J Med Genet A 2020;182:183–188.
- Feng D, Xie J. Aberrant splicing in neurological diseases. Wiley Interdiscip Rev RNA 2013;4:631–649.
- Linder B, Fischer U, Gehring NH. mRNA metabolism and neuronal disease. FEBS Lett 2015;589:1598–1606.
- Bain JM, Cho MT, Telegrafi A, et al. . Variants in HNRNPH2 on the X chromosome are associated with a neurodevelopmental disorder in females. Am J Hum Genet 2016;99:728–734.
- Harmsen S, Buchert R, Mayatepek E, Haack TB, Distelmaier F. Bain type of X-linked syndromic mental retardation in boys. Clin Genet 2019;95:734–735.
- Piton A, Gauthier J, Hamdan F, et al. . Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia. Mol Psychiatry 2011;16:867–880.
- Sparrow S, Balla D, Cicche H. Vineland Adaptive Behavior Scales-Interview Edition Survey Form Manual. Circle Pines: American Guidance Service, Inc.; 1984.
- Sparrow S, Cicchetti D, Saulnier C. Vineland Adaptive Behavior Scales Manual (Vineland-3). Bloomington: Pearson; 2016.
- Rutter M, Bailey A, Lord C. The Social Communication Questionnaire: Manual. Torrance: Western Psychological Services; 2003.
- Constantino JN, Gruber CP. Social Responsiveness Scale Second Edition (SRS-2): Manual. Torrance: Western Psychological Services (WPS); 2012.
- Dunn W. Child Sensory Profile–2 User's Manual. Bloomington: Pearson; 2014.
- Dunn W. Sensory Profile: User's Manual. San Antonio: Psychological Corporation; 1999.
- White BP, Mulligan S, Merrill K, Wright J. An examination of the relationships between motor and process skills and scores on the sensory profile. Am J Occup Ther 2007;61:154–160.
- Simpson K, Adams D, Alston-Knox C, Heussler HS, Keen D. Exploring the sensory profiles of children on the autism spectrum using the short sensory profile-2 (SSP-2). J Autism Dev Disord 2019;49:2069–2079.
- Reynolds C, Kamphaus R. BASC-3 Behavioral and Emotional Screening System Manual. Circle Pines: Pearson; 2015.
- Haley S, Coster W, Dumas H, Fragala-Pinkham M, Moed R. PEDI-CAT: Development, Standardization and Administration Manual. Boston: Boston University; 2012.
- Jepsen WM, Ramsey K, Szelinger S, et al. . Two additional males with X-linked, syndromic mental retardation carry de novo mutations in HNRNPH2. Clin Genet 2019;96:183–185.
- Pavao SL, Rocha N. Sensory processing disorders in children with cerebral palsy. Infant Behav Dev 2017;46:1–6.
- Geuens T, Bouhy D, Timmerman V. The hnRNP family: insights into their role in health and disease. Hum Genet 2016;135:851–867.
- Han SP, Tang YH, Smith R. Functional diversity of the hnRNPs: past, present and perspectives. Biochem J 2010;430:379–392.
- Van Dusen CM, Yee L, McNally LM, McNally MT. A glycine-rich domain of hnRNP H/F promotes nucleocytoplasmic shuttling and nuclear import through an interaction with transportin 1. Mol Cell Biol 2010;30:2552–2562.
- Pilch J, Koppolu AA, Walczak A, et al. . Evidence for HNRNPH1 being another gene for Bain type syndromic mental retardation. Clin Genet 2018;94:381–385.
- Reichert SC, Li R, Turner SA, et al. . HNRNPH1‐related syndromic intellectual disability: seven additional cases suggestive of a distinct syndromic neurodevelopmental syndrome. Clin Genet 2020;98:91–98.
- Dvinge H, Kim E, Abdel-Wahab O, Bradley RK. RNA splicing factors as oncoproteins and tumour suppressors. Nat Rev Cancer 2016;16:413–430.
- Nussbacher JK, Tabet R, Yeo GW, Lagier-Tourenne C. Disruption of RNA metabolism in neurological diseases and emerging therapeutic interventions. Neuron 2019;102:294–320.
- Finsterer J, Stöllberger C, Keller H, Laccone F. Variants in HNRNPDL and SETX not necessarily indicate familial amyotrophic lateral sclerosis or limb girdle muscular dystrophy 1G in acute muscular respiratory failure. J Neurosci Rural Pract 2020;11:353.
- Duijkers FA, McDonald A, Janssens GE, et al. . HNRNPR variants that impair homeobox gene expression drive developmental disorders in humans. Am J Hum Genet 2019;104:1040–1059.
- Farmer C, Adedipe D, Bal V, Chlebowski C, Thurm A. Concordance of the Vineland Adaptive Behavior Scales, second and third editions. J Intellect Disabil Res 2020;64:18–26.
Source: PubMed