The clinical-phenotype continuum in DYNC1H1-related disorders-genomic profiling and proposal for a novel classification

Lena-Luise Becker, Hormos Salimi Dafsari, Jens Schallner, Dalia Abdin, Michael Seifert, Florence Petit, Thomas Smol, Levinus Bok, Lance Rodan, Ingrid Krapels, Stephanie Spranger, Bernhard Weschke, Katherine Johnson, Volker Straub, Angela M. Kaindl, Nataliya Di Donato, Maja von der Hagen*, Sebahattin Cirak*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

12 Citations (Web of Science)

Abstract

Mutations in the cytoplasmic dynein 1 heavy chain gene (DYNC1H1) have been identified in rare neuromuscular (NMD) and neurodevelopmental (NDD) disorders such as spinal muscular atrophy with lower extremity dominance (SMALED) and autosomal dominant mental retardation syndrome 13 (MRD13). Phenotypes and genotypes of ten pediatric patients with pathogenicDYNC1H1variants were analyzed in a multi-center study. Data mining of large-scale genomic variant databases was used to investigate domain-specific vulnerability and conservation ofDYNC1H1. We identified ten patients with nine novel mutations in theDYNC1H1gene. These patients exhibit a broad spectrum of clinical findings, suggesting an overlapping disease manifestation with intermixed phenotypes ranging from neuropathy (peripheral nervous system, PNS) to severe intellectual disability (central nervous system, CNS). Genomic profiling of healthy and patient variant datasets underlines the domain-specific effects of genetic variation inDYNC1H1, specifically on toleration towards missense variants in the linker domain. A retrospective analysis of all published mutations revealed domain-specific genotype-phenotype correlations, i.e., mutations in the dimerization domain with reductions in lower limb strength inDYNC1H1-NMD and motor domain with cerebral malformations inDYNC1H1-NDD. We highlight that the current classification into distinct disease entities does not sufficiently reflect the clinical disease manifestation that clinicians face in the diagnostic work-up ofDYNC1H1-related disorders. We propose a novel clinical classification forDYNC1H1-related disorders encompassing a spectrum fromDYNC1H1-NMD with an exclusive PNS phenotype toDYNC1H1-NDD with concomitant CNS involvement.

Original languageEnglish
Pages (from-to)1003-1017
Number of pages15
JournalJournal of Human Genetics
Volume65
Issue number11
DOIs
Publication statusPublished - Nov 2020

Keywords

  • SPINAL MUSCULAR-ATROPHY
  • LOWER-EXTREMITY
  • INTELLECTUAL DISABILITY
  • CORTICAL DEVELOPMENT
  • GENETIC-VARIATION
  • MUTATIONS
  • DYNC1H1
  • SPECTRUM
  • MALFORMATIONS
  • VARIANTS

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