Alternative titles; symbols
ORPHA: 178469; DO: 0070043;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 14q32.31 | Cortical dysplasia, complex, with other brain malformations 13 | 614563 | Autosomal dominant | 3 | DYNC1H1 | 600112 |
A number sign (#) is used with this entry because of evidence that complex cortical dysplasia with other brain malformations-13 (CDCBM13) is caused by heterozygous mutation in the DYNC1H1 gene (600112) on chromosome 14q32.
Complex cortical dysplasia with other brain malformations-13 (CDCBM13) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development. Brain imaging shows variable neuronal migration defects resulting in cortical malformations, including pachygyria. More variable features include early-onset seizures and dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by Willemsen et al., 2012 and Poirier et al., 2013).
For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).
Vissers et al. (2010) reported a 4-year-old boy with global developmental delay. He showed hypotonia at age 6 months, followed by delayed psychomotor development. Mild dysmorphic features included prominent forehead, plagiocephaly, hypotonic face with downslanting palpebral fissures, and short, broad hands and feet. Brain MRI was reported as normal. His parents were unaffected. Follow-up of the patient at age 6 years by Willemsen et al. (2012) noted that he had hypotonia, hyporeflexia, and broad-based waddling gait with toe walking. Reevaluation of brain MRI showed signs of bilateral cortical malformation with deficient gyration of the frontal lobes and an area suggestive of focal cortical dysplasia. Willemsen et al. (2012) also reported a 51-year-old woman with severe mental retardation and an inability to walk or speak. She had short stature, microcephaly, clubfeet, and small hands and feet with short toes. Craniofacial features included brachycephaly, prominent forehead, hypertelorism, deep-set eyes, wide mouth with everted lower lip, and downturned corners of the mouth. She developed generalized seizures at age 3 years. Other features included kyphoscoliosis, spastic tetraplegia, and swallowing difficulties. Cerebral CT scan at the age 46 years showed enlarged ventricles and clear signs of cortical malformation with wide opercular regions and an abnormal flat cortex with only a few simple and shallow sulci; MRI scan was not possible.
Poirier et al. (2013) reported 8 unrelated patients with moderate to severely impaired intellectual development associated with cortical brain malformations on MRI. All but 1 had seizures, most of early onset. Three had microcephaly, 3 were bedridden with spastic tetraplegia, 2 were described as having 'awkwardness' on neurologic examination, and 3 patients had foot deformities consistent with axonal neuropathy. Brain MRI showed predominantly posterior pachygyria, and some patients also had frontal polymicrogyria or nodular heterotopia. Several patients also had other brain abnormalities, including dysmorphic basal ganglia and hypoplasia of the corpus callosum, brainstem, and/or cerebellum.
The majority of reported patients with CDCBM13 had de novo mutations in the DYNC1H1 gene, consistent with sporadic occurrence of the disorder. One family with a mild phenotype showed autosomal dominant inheritance (Poirier et al., 2013).
By family-based exome sequencing of 10 case-parent trios with global developmental delay, Vissers et al. (2010) identified a de novo heterozygous mutation in the DYNC1H1 gene (H3822P; 600112.0002) in 1 patient. Willemsen et al. (2012) identified a second de novo heterozygous mutation in the DYNC1H1 gene (E1518K; 600112.0003) in a 51-year-old woman with severe intellectual disability since infancy and an inability to walk or speak. Willemsen et al. (2012) noted that DYNC1H1 interacts with LIS1 (601545), haploinsufficiency of which results in the severe neuronal migration disorder lissencephaly-1 (607432), and that Dync1h1 mutant mice show neuronal migration defects (Ori-McKenney and Vallee, 2011), providing evidence of the pathogenicity of the mutations. Willemsen et al. (2012) also noted that their 2 patients showed variable signs consistent with peripheral neuropathy and that some patients with CMT2O (614228) (Weedon et al., 2011) carrying a DYNC1H1 mutation showed learning difficulties, indicating that DYNC1H1 mutations may result in a broad neurologic phenotypic spectrum.
Poirier et al. (2013) identified 8 different de novo heterozygous mutations in the DYNC1H1 gene (see, e.g., 600112.0007-600112.0009) in 8 unrelated patients ascertained for evaluation due to malformations of cortical development. Mutations in the first several patients were found by whole-exome sequencing, whereas subsequent patients were identified by direct sequencing of this gene in a larger cohort of affected individuals. In vitro functional expression studies of 2 of the variants showed that the mutant proteins had decreased microtubule binding affinity compared to wildtype. In addition, there was 1 family in which a mother and her 2 children carried a missense variant (K3241T): 1 of the children had mild intellectual disability, but the mother and the other child had normal cognition. All 3 were normocephalic, showed posterior pachygyria, and had focal seizures. No functional studies were performed on the K3241T variant, which occurred at a nonconserved residue.
Jamuar et al. (2014) used a customized panel of known and candidate genes associated with brain malformations to apply targeted high-coverage sequencing (depth greater than or equal to 200x) to leukocyte-derived DNA samples from 158 individuals with brain malformations. They found potentially causal mutations in the candidate gene DYNC1H1 in 2 individuals with pachygyria; in a parallel study they had found de novo mutations in DYNC1H1 in 2 other individuals with pachygyria. The 4 individuals had strikingly similar MRI findings, with posterior-predominant pachygyria, thickened cortex in the perisylvian region, and mildly dysmorphic corpus callosum. One of the individuals identified in the report of Jamuar et al. (2014) had onset of seizures at age 5 years and mental and motor retardation. The other had dysarthria and cognitive delay but normal vision, hearing, and head circumference, and no seizures.
Jamuar, S. S., Lam, A. N., Kircher, M., D'Gama, A. M., Wang, J., Barry, B. J., Zhang, X., Hill, R. S., Partlow, J. N., Rozzo, A., Servattalab, S., Mehta, B. K., and 20 others. Somatic mutations in cerebral cortical malformations. New Eng. J. Med. 371: 733-743, 2014. [PubMed: 25140959] [Full Text: https://doi.org/10.1056/NEJMoa1314432]
Ori-McKenney, K. M., Vallee, R. B. Neuronal migration defects in the Loa dynein mutant mouse. Neural Dev. 6: 26, 2011. Note: Electronic Article. [PubMed: 21612657] [Full Text: https://doi.org/10.1186/1749-8104-6-26]
Poirier, K., Lebrun, N., Broix, L., Tian, G., Saillour, Y., Boscheron, C., Parrini, E., Valence, S., Saint Pierre, B., Oger, M., Lacombe, D., Genevieve, D., and 23 others. Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly. Nature Genet. 45: 639-647, 2013. Note: Erratum: Nature Genet. 45: 962 only, 2013. [PubMed: 23603762] [Full Text: https://doi.org/10.1038/ng.2613]
Vissers, L. E. L. M., de Ligt, J., Gilissen, C., Janssen, I., Steehouwer, M., de Vries, P., van Lier, B., Arts, P., Wieskamp, N., del Rosario, M., van Bon, B. W. M., Hoischen, A., de Vries, B. B. A., Brunner, H. G., Veltman, J. A. A de novo paradigm for mental retardation. Nature Genet. 42: 1109-1112, 2010. [PubMed: 21076407] [Full Text: https://doi.org/10.1038/ng.712]
Weedon, M. N., Hastings, R., Caswell, R., Xie, W., Paszkiewicz, K., Antoniadi, T., Williams, M., King, C., Greenhalgh, L., Newbury-Ecob, R., Ellard, S. Exome sequencing identifies a DYNC1H1 mutation in a large pedigree with dominant axonal Charcot-Marie-Tooth disease. Am. J. Hum. Genet. 89: 308-312, 2011. [PubMed: 21820100] [Full Text: https://doi.org/10.1016/j.ajhg.2011.07.002]
Willemsen, M. H., Vissers, L. E. L., Willemsen, M. A. A. P., van Bon, B. W. M., Kroes, T., de Ligt, J., de Vries, B. B., Schoots, J., Lugtenberg, D., Hamel, B. C. J., van Bokhoven, H., Brunner, H. G., Veltman, J. A., Kleefstra, T. Mutations in DYNC1H1 cause severe intellectual disability with neuronal migration defects. J. Med. Genet. 49: 179-183, 2012. [PubMed: 22368300] [Full Text: https://doi.org/10.1136/jmedgenet-2011-100542]