ORPHA: 2510; DO: 0110719;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 20p13 | Warburg micro syndrome 4 | 615663 | Autosomal recessive | 3 | TBC1D20 | 611663 |
A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-4 (WARBM4) is caused by homozygous mutation in the TBC1D20 gene (611663) on chromosome 20p13.
Warburg Micro syndrome (WARBM) is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severely impaired intellectual development, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010).
For a discussion of genetic heterogeneity of Warburg Micro syndrome, see WARBM1 (600118).
Liegel et al. (2013) studied 7 patients from 5 families with Warburg Micro syndrome due to mutations in the TBC1D20 gene who showed the same range of clinical features observed in WARBM patients with mutations in the RAB3GAP1 (602536), RAB3GAP2 (609275), and RAB18 (602207) genes. Shortly after birth, patients presented with congenital cataracts, microphthalmia, microcornea, and small atonic pupils. Despite cataract surgery, they had poor vision due to optic atrophy, and several affected children also developed glaucoma. All patients with TBC1D20 mutations had severe to profound developmental delay: they did not learn to walk and spoke only 4 to 5 words at most. They also displayed autistic features. Patients had normal head circumferences at birth but developed postnatal microcephaly. Facial features included deep-set eyes, ptosis, broad nasal bridge, relatively narrow mouth, low anterior hairline, and prominent subnasal region. Affected boys exhibited micropenis and cryptorchidism. In the first year of life, all affected individuals had severe axial hypotonia, and then gradually developed lower and upper limb spasticity, resulting in spastic quadriplegia. Cranial MRIs in 4 patients showed predominantly frontal polymicrogyria, corpus callosum hypogenesis particularly involving the splenium, widened lateral ventricles, and megacisterna magna due to cerebellar vermis hypoplasia; follow-up MRIs in 2 of the patients showed atrophy of the cerebellar vermis and hemispheres.
Abdel-Hamid et al. (2020) reported 3 sibs, aged 1, 7 and 9 years, with WARBM4. All 3 sibs had infantile cataracts, microcornea, microphthalmia, and abnormal visual evoked potentials. Two of the sibs also had optic atrophy. One sib had severe developmental delay, spastic quadriparesis, and myoclonic seizures, and the other 2 sibs had moderate developmental delay and spastic paraparesis. On sib had an absent clitoris and scoliosis, another sib had hypoplastic labia and bilateral single palmar crease, and the other sib had pectus excavatum. Neuroimaging in the 3 sibs showed polymicrogyria, thin corpus callosum, dilated ventricles, and white matter dysmyelination. Neuroimaging showed cerebellar atrophy in 2 sibs and faint bilateral basal ganglia calcifications in the other sib.
In a cohort of 77 patients with a spectrum of Warburg Micro disorders, Liegel et al. (2013) analyzed the candidate gene TBC1D20 and identified homozygous mutations in 7 patients diagnosed with WARBM from 5 families of different ethnic origins (611663.0001-611663.0005). The cohort included 59 cases of 'typical' WARBM, 5 cases diagnosed with Martsolf syndrome (212720), and 13 atypical cases that had been described by Handley et al. (2013).
In 3 Egyptian sibs, born to consanguineous parents, with WARBM4, Abdel-Hamid et al. (2020) identified homozygosity for the R67X mutation in the TBC1D20 gene (611663.0001) that was previously identified by Liegel et al. (2013). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents.
Abdel-Hamid, M. S., Abdel-Ghafar, S. F., Ismail, S. R., Desouky, L. M., Issa, M. Y., Effat, L. K., Zaki, M. S. Micro and Martsolf syndromes in 34 new patients: refining the phenotypic spectrum and further molecular insights. Clin. Genet. 98: 445-456, 2020. [PubMed: 32740904] [Full Text: https://doi.org/10.1111/cge.13825]
Handley, M. T., Morris-Rosendahl, D. J., Brown, S., Macdonald, F., Hardy, C., Bem, D., Carpanini, S. M., Borck, G., Martorell, L., Izzi, C., Faravelli, F., Accorsi, P., and 23 others. Mutation spectrum in RAB3GAP1, RAB3GAP2, and RAB18 and genotype-phenotype correlations in Warburg Micro syndrome and Martsolf syndrome. Hum. Mutat. 34: 686-696, 2013. [PubMed: 23420520] [Full Text: https://doi.org/10.1002/humu.22296]
Liegel, R. P., Handley, M. T., Ronchetti, A., Brown, S., Langemeyer, L., Linford, A., Chang, B., Morris-Rosendahl, D. J., Carpanini, S., Posmyk, R., Harthill, V., Sheridan, E., and 11 others. Loss-of-function mutations in TBC1D20 cause cataracts and male infertility in blind sterile mice and Warburg Micro syndrome in humans. Am. J. Hum. Genet. 93: 1001-1014, 2013. [PubMed: 24239381] [Full Text: https://doi.org/10.1016/j.ajhg.2013.10.011]
Morris-Rosendahl, D. J., Segel, R., Born, A. P., Conrad, C., Loeys, B., Brooks, S. S., Muller, L., Zeschnigk, C., Botti, C., Rabinowitz, R., Uyanik, G., Crocq, M.-A., Kraus, U., Degen, I., Faes, F. New RAB3GAP1 mutations in patients with Warburg Micro syndrome from different ethnic backgrounds and a possible founder effect in the Danish. Europ. J. Hum. Genet. 18: 1100-1106, 2010. [PubMed: 20512159] [Full Text: https://doi.org/10.1038/ejhg.2010.79]