DYNC1H1 (OMIM #600112) encodes the heavy chain 1 of cytoplasmic dynein and controls microtubule binding as well as the recruitment of dynein components involved in retrograde axonal transport in neurons [1,2]. Mutations in DYNC1H1 are associated with a wide spectrum of clinical manifestations including spinal muscular atrophy (SMA) [1,3,4,5], hereditary motor and sensory neuropathies [6], hereditary spastic paraplegia [7], malformations of cortical development (MCD), epilepsy, and intellectual disability [2,8,9]. Axonal defects are likely due to DYNC1H1’s role as the sole motor unit responsible for retrograde transport in axons [10]. Neuronal migration defects are likely due to DYNC1H1’s direct association with LIS1 (Lissencephaly 1/platelet-activating factor acetylhydrolase isoform 1B, alpha subunit, PAFAH1B1) which is known to be critically required for normal neuronal migration during cortical development [9,11]. Reports of pediatric patients with DYNC1H1 mutations have previously been published. The authors of those reports describe patients with a variety of symptoms including developmental delay, epilepsy, muscle weakness and wasting, microcephaly, spastic quadriplegia, foot deformities, and motor and sensory neuropathies [10]. Magnetic Resonance Imaging of those patients identified cortical malformations including pachygyria and polymicrogyria. Here we describe a patient with a DYNC1H1 variant and symptoms not previously associated with this gene. Our observations expand the spectrum of manifestations of DYNC1H1 mutations in humans.

We describe a patient under the care of physicians at Cincinnati Children’s Hospital Medical Center (CCHMC). All patient and parents were enrolled in a study upon informed written consent and assent as approved by the CCHMC Institutional Review Board (2014-3789, approved on 24 September 2015). Exome sequencing was performed at the CCHMC DNA Sequencing and Genotyping Core. In brief, genomic DNA was enriched with the NimbleGen EZ Exome V2 kit (Roche NimbleGen, Madison, WI, USA) and the exome library was sequenced using Illumina’s Hi Seq 2000 (Illumina, San Diego, CA, USA). Alignment and variant detection was performed using the Broad Institute’s web-based Genome Analysis Toolkit (GATK; [12]). Patient examinations were performed following best-practice guidelines and standard equipment.

The spectrum of disease caused by mutations in DYNC1H1 has become evident with the advent of wide-spread genomic sequencing. We present here a patient with a mutation in the motor domain of DYNC1H1 with a varied clinical presentation including failure to thrive, oral dysphagia, gut dysmotility, congenital cataracts, and developmental delay. MRI studies demonstrated bifrontal polymicrogyria. While the broad findings of developmental delay and polymicrogyria are consistent with previously reported patients with mutations in DYNC1H1, this report suggests other systems can be affected by dynein mutations. A very recent report also identified this mutation in a patient with many similar phenotypes, including congenital cataracts, microcephaly and failure to thrive [17]. Additionally, a patient with hereditary spastic paraplegia was found to develop bilateral cataracts in childhood [7]. As DYNC1H1 is expressed in the elongating fiber cells of the lens and possibly traffics vesicles along microtubules for reorganization of the fiber cell, it is possible that mutations in the motor domain disrupt the development of the lens and result in cataracts [18]. In addition, this is the first report of a DYNC1H1 patient to display gut dysmotility with evidence of a mild enteric neuropathy. While the role of DYNC1H1 in the enteric nervous system or neural crest cell migration into the gut is unknown, previously reported patients with mutations in DYNC1H1 have exhibited peripheral motor and sensory neuropathies, which may be related to the proband’s phenotype [1]. Tissue-specific loss-of-function mutations in DYNC1H1 will aide in determining the true requirement of DYNC1H1 in the lens and enteric nervous system.

The mechanism underlying the wide range of clinical presentations in patients with DYNC1H1 mutations has yet to be determined. Several mouse models with loss of Dync1h1 function exist. The first homozygous knockout Dync1h1 mouse died in early gestation (prior to embryonic day 8.5) due to abnormalities in the Golgi apparatus, endosome, lysosome, and massive defects in mitosis in the inner cell mass [19]. Later, ENU mutagenesis screens produced two independent point mutations in the stem domain of Dync1h1. Legs-at-odd-angles (Loa) and Cramping1 (Cra1) heterozygous mice display a dominant motor weakness and sensory neuropathy phenotype characterized by a massive decrease in motor neurons (20%–50%) by gestational age E18.5 leading to paralysis and death within 24 h [20,21]. A subsequent analysis showed that Loa mutant mice also had neuronal migration defects in the cortex [22]. A radiation-induced knockout, Sprawling (Swl), contains a 9 bp deletion in the stem domain of Dync1h1 resulting in a dominant phenotype with early onset sensory neuropathy and loss of muscle spindles in hind-limb muscles [23]. However, to date a mouse mutant with mutations in the Dync1h1 motor domain has not been identified. Our patient’s phenotype is consistent with other patients with mutations in the motor domain, producing a largely MCD/epilepsy phenotype. As previously reported [1,24], patients with mutations in the stem domain are significantly more likely to develop motor and sensory neuropathies, while patients with mutations in the motor domain are more likely to develop malformations of cortical development and epilepsy, though these genotypes show some degree of overlapping phenotypes (Figure 2E). Scoto et al. recently highlighted the overlap in phenotypes of tail and motor domain mutations in a large cohort of SMA-LED patients with comorbid MCD [24]. As only the tail domain has been mutated in mouse models of a dyneinopathy, targeted mutations involving only the motor domain in mice will shed light on the role of each domain in the disease.