The expanding clinical and genetic spectrum of DYNC1H1-related disorders
Authors: Möller Birk , Becker Lena-Luise , Saffari Afshin , Afenjar Alexandra , Coci Emanuele G , Williamson Rachel , Ward-Melver Catherine , Gibaud Marc , Sedláčková Lucie , Laššuthová Petra , Libá Zuzana , Vlčková Markéta , William Nancy , Klee Eric W , Gavrilova Ralitza H , Lévy Jonathan , Capri Yline , Scavina Mena , Körner Robert Walter , Valivullah Zaheer , Weiß Claudia , Möller Greta Marit , Frazier Zoë , Roberts Amy , Gener Blanca , Scala Marcello , Striano Pasquale , Zara Federico , Thiel Moritz , Sinnema Margje , Kamsteeg Erik-Jan , Donkervoort Sandra , Duboc Veronique , Zaafrane-Khachnaoui Khaoula , Elkhateeb Nour , Selim Laila , Margot Henri , Marin Victor , Beneteau Claire , Isidor Bertrand , Cogne Benjamin , Keren Boris , Küsters Benno , Beggs Alan H , Sveden Abigail , Chopra Maya , Genetti Casie A , Nicolai Joost , Dötsch Jörg , Koy Anne , Bönnemann Carsten G , von der Hagen Maja , von Kleist-Retzow Jürgen-Christoph , Voermans Nicol C , Jungbluth Heinz , Dafsari Hormos Salimi 
Published: June 2024

Intracellular trafficking involves an intricate machinery of motor complexes, including the dynein complex, to shuttle cargo for autophagolysosomal degradation. Deficiency in dynein axonemal chains, as well as cytoplasmic light and intermediate chains, have been linked with ciliary dyskinesia and skeletal dysplasia. The cytoplasmic dynein 1 heavy chain protein (DYNC1H1) serves as a core complex for retrograde trafficking in neuronal axons. Dominant pathogenic variants in DYNC1H1 have been previously implicated in peripheral neuromuscular disorders (NMD) and neurodevelopmental disorders (NDD). As heavy-chain dynein is ubiquitously expressed, the apparent selectivity of heavy chain dyneinopathy for motor neuronal phenotypes remains currently unaccounted for. Here, we aimed to evaluate the full DYNC1H1-related clinical, molecular and imaging spectrum, including multisystem features and novel phenotypes presenting throughout life.

We identified 47 cases from 43 families with pathogenic heterozygous variants in DYNC1H1 (aged 0–59 years) and collected phenotypic data via a comprehensive standardized survey and clinical follow-up appointments. Most patients presented with divergent and previously unrecognized neurological and multisystem features, leading to significant delays in genetic testing and establishing the correct diagnosis. Neurological phenotypes include novel autonomic features, previously rarely described behavioral disorders, movement disorders and periventricular lesions. Sensory neuropathy was identified in nine patients (median age of onset 10.6 years), of which five were only diagnosed after the second decade of life, and three had a progressive age-dependent sensory neuropathy.

Novel multisystem features included primary immunodeficiency, bilateral sensorineural hearing loss, organ anomalies and skeletal manifestations, resembling the phenotypic spectrum of other dyneinopathies. We also identified an age-dependent biphasic disease course with developmental regression in the first decade and, following a period of stability, neurodegenerative progression after the second decade of life. Of note, we observed several cases in whom neurodegeneration appeared to be prompted by intercurrent systemic infections with double-stranded DNA viruses (Herpesviridae) or single-stranded RNA viruses (Ross River fever, SARS-CoV-2). Moreover, the disease course appeared to be exacerbated by viral infections regardless of age and/or severity of neurodevelopmental disorder manifestations, indicating a role of dynein in anti-viral immunity and neuronal health.

In summary, our findings expand the clinical, imaging and molecular spectrum of pathogenic DYNC1H1 variants beyond motor neuropathy disorders and suggest a life-long continuum and age-related progression due to deficient intracellular trafficking. This study will facilitate early diagnosis and improve counselling and health surveillance of affected patients.