Universität zu Köln

Becker, Lena-Luise ORCID: 0000-0003-4622-8695, Dafsari, Hormos Salimi, Schallner, Jens, Abdin, Dalia, Seifert, Michael, Petit, Florence, Smol, Thomas ORCID: 0000-0002-0119-5896, Bok, Levinus, Rodan, Lance, Krapels, Ingrid, Spranger, Stephanie, Weschke, Bernhard, Johnson, Katherine, Straub, Volker, Kaindl, Angela M., Di Donato, Nataliya ORCID: 0000-0001-9439-4677, von der Hagen, Maja and Cirak, Sebahattin (2020). The clinical-phenotype continuum inDYNC1H1-related disorders-genomic profiling and proposal for a novel classification. J. Hum. Genet., 65 (11). S. 1003 - 1018. LONDON: SPRINGERNATURE. ISSN 1435-232X

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Becker, Lena-Luise UNSPECIFIED orcid.org/0000-0003-4622-8695 UNSPECIFIED Dafsari, Hormos Salimi UNSPECIFIED UNSPECIFIED UNSPECIFIED Schallner, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdin, Dalia UNSPECIFIED UNSPECIFIED UNSPECIFIED Seifert, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Petit, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Smol, Thomas UNSPECIFIED orcid.org/0000-0002-0119-5896 UNSPECIFIED Bok, Levinus UNSPECIFIED UNSPECIFIED UNSPECIFIED Rodan, Lance UNSPECIFIED UNSPECIFIED UNSPECIFIED Krapels, Ingrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Spranger, Stephanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Weschke, Bernhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Johnson, Katherine UNSPECIFIED UNSPECIFIED UNSPECIFIED Straub, Volker UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaindl, Angela M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Di Donato, Nataliya UNSPECIFIED orcid.org/0000-0001-9439-4677 UNSPECIFIED von der Hagen, Maja UNSPECIFIED UNSPECIFIED UNSPECIFIED Cirak, Sebahattin UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-323416
DOI:	10.1038/s10038-020-0803-1
Journal or Publication Title:	J. Hum. Genet.
Volume:	65
Number:	11
Page Range:	S. 1003 - 1018
Date:	2020
Publisher:	SPRINGERNATURE
Place of Publication:	LONDON
ISSN:	1435-232X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPINAL MUSCULAR-ATROPHY; LOWER-EXTREMITY; INTELLECTUAL DISABILITY; CORTICAL DEVELOPMENT; GENETIC-VARIATION; MUTATIONS; DYNC1H1; SPECTRUM; MALFORMATIONS; VARIANTS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/32341