#617391
Table of Contents
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-54 (DEE54) is caused by heterozygous mutation in the HNRNPU gene (602869) on chromosome 1q44.
Developmental and epileptic encephalopathy-54 (DEE54) is a severe neurodevelopmental disorder characterized by delayed psychomotor development, early-onset refractory seizures that are often initially febrile but later afebrile, and severe intellectual disability (summary by de Kovel et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Carvill et al. (2013) reported a 33-year-old man (patient T162) with DEE54. He had delayed development before seizure onset as well as severe intellectual disability with regression. He had onset of atonic seizures at age 2 years, followed by atypical absence seizures, myoclonic jerks, nonconvulsive status epilepticus, and tonic and tonic-clonic seizures. EEG showed multiple abnormalities, including generalized spike and polyspike waves, diffuse slowing, slow spike waves, and generalized paroxysmal fast activity.
Hamdan et al. (2014) reported a 3.5-year-old boy (patient 1464.524) with DEE54. Clinical details were sparse, but the child was noted to have severe intellectual disability, early-onset borderline microcephaly, autistic features, and seizures. He was hypotonic and was unable to speak or walk. Brain imaging showed enlarged ventricles and myelination delay.
De Kovel et al. (2016) reported a girl (patient 2012D06376) with DEE54. She had developmental delay in early infancy and presented with febrile seizures at age 8 months. At age 2 years, she did not speak. Other features included hypotonia, hyperlaxity, deep-set eyes with epicanthal folds, narrow palate, gray sclerae, and a short second digit on each hand. Brain imaging suggested delayed myelination, and EEG showed epileptiform activity.
The heterozygous mutations in the HNRNPU gene that were identified in patients with DEE54 by Hamdan et al. (2014) and De Kovel et al. (2016) occurred de novo.
In a 33-year-old man (patient T162) with DEE54, Carvill et al. (2013) identified a heterozygous nonsense mutation in the HNRNPU gene (Y805X; 602869.0001). The mutation was not present in the mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In a 3.5-year-old boy (patient 1464.524) with DEE54, Hamdan et al. (2014) identified a de novo heterozygous nonsense mutation in the HNRNPU gene (Q171X; 602869.0002). The mutation was not found in the Exome Variant Server database; functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.
In a girl (patient 2012D06376) with DEE54, de Kovel et al. (2016) identified a de novo frameshift mutation in the HNRNPU gene (602869.0003). The mutation was found by sequencing candidate genes for epileptic encephalopathy in 359 patients and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In an 11-year-old girl (trio hv) with DEE54, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous small insertion/deletion in a splice acceptor site of the HNRNPU gene, predicted to result in a modified protein. The patient was part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. The patient had previously been reported by Need et al. (2012) as also carrying a de novo heterozygous mutation in the SMAD1 gene (601595). Functional studies of the variants and studies of patient cells were not performed. The patient had delayed development before onset of febrile seizures at age 9 months. She later developed multiple types of refractory afebrile seizures. At age 11, she was nonverbal with severe intellectual disability, autistic features, aggressive behavior, and incontinence.
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187, images, related citations] [Full Text]
de Kovel, C. G. F., Brilstra, E. H., van Kempen, M. J. A., van't Slot, R., Nijman, I. J., Afawi, Z., De Jonghe, P., Djemie, T., Guerrini, R., Hardies, K., Helbig, I., Hendrickx, R., and 13 others. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Molec. Genet. Genomic Med. 4: 568-580, 2016. [PubMed: 27652284, images, related citations] [Full Text]
Epi4K Consortium and Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501: 217-221, 2013. [PubMed: 23934111, images, related citations] [Full Text]
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., Henrion, E., Dionne-Laporte, A., Fougerat, A., Pshezhetsky, A. V., Venkateswaran, S., Rouleau, G. A., Michaud, J. L. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10: e1004772, 2014. Note: Electronic Article. [PubMed: 25356899, images, related citations] [Full Text]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936, images, related citations] [Full Text]
Alternative titles; symbols
ORPHA: 1934; DO: 0080418;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q44 | Developmental and epileptic encephalopathy 54 | 617391 | Autosomal dominant | 3 | HNRNPU | 602869 |
A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-54 (DEE54) is caused by heterozygous mutation in the HNRNPU gene (602869) on chromosome 1q44.
Developmental and epileptic encephalopathy-54 (DEE54) is a severe neurodevelopmental disorder characterized by delayed psychomotor development, early-onset refractory seizures that are often initially febrile but later afebrile, and severe intellectual disability (summary by de Kovel et al., 2016).
For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.
Carvill et al. (2013) reported a 33-year-old man (patient T162) with DEE54. He had delayed development before seizure onset as well as severe intellectual disability with regression. He had onset of atonic seizures at age 2 years, followed by atypical absence seizures, myoclonic jerks, nonconvulsive status epilepticus, and tonic and tonic-clonic seizures. EEG showed multiple abnormalities, including generalized spike and polyspike waves, diffuse slowing, slow spike waves, and generalized paroxysmal fast activity.
Hamdan et al. (2014) reported a 3.5-year-old boy (patient 1464.524) with DEE54. Clinical details were sparse, but the child was noted to have severe intellectual disability, early-onset borderline microcephaly, autistic features, and seizures. He was hypotonic and was unable to speak or walk. Brain imaging showed enlarged ventricles and myelination delay.
De Kovel et al. (2016) reported a girl (patient 2012D06376) with DEE54. She had developmental delay in early infancy and presented with febrile seizures at age 8 months. At age 2 years, she did not speak. Other features included hypotonia, hyperlaxity, deep-set eyes with epicanthal folds, narrow palate, gray sclerae, and a short second digit on each hand. Brain imaging suggested delayed myelination, and EEG showed epileptiform activity.
The heterozygous mutations in the HNRNPU gene that were identified in patients with DEE54 by Hamdan et al. (2014) and De Kovel et al. (2016) occurred de novo.
In a 33-year-old man (patient T162) with DEE54, Carvill et al. (2013) identified a heterozygous nonsense mutation in the HNRNPU gene (Y805X; 602869.0001). The mutation was not present in the mother; DNA from the father was unavailable. Functional studies of the variant and studies of patient cells were not performed. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In a 3.5-year-old boy (patient 1464.524) with DEE54, Hamdan et al. (2014) identified a de novo heterozygous nonsense mutation in the HNRNPU gene (Q171X; 602869.0002). The mutation was not found in the Exome Variant Server database; functional studies of the variant and studies of patient cells were not performed. The patient was part of a cohort of 41 child-parent trios, in which the child had intellectual disability, who underwent exome sequencing.
In a girl (patient 2012D06376) with DEE54, de Kovel et al. (2016) identified a de novo frameshift mutation in the HNRNPU gene (602869.0003). The mutation was found by sequencing candidate genes for epileptic encephalopathy in 359 patients and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay. The patient was part of a larger cohort of 500 patients with epileptic encephalopathies who underwent targeted sequencing of candidate genes.
In an 11-year-old girl (trio hv) with DEE54, the Epi4K Consortium and Epilepsy Phenome/Genome Project (2013) identified a de novo heterozygous small insertion/deletion in a splice acceptor site of the HNRNPU gene, predicted to result in a modified protein. The patient was part of a larger cohort of 264 probands with epileptic encephalopathy who underwent exome sequencing. The patient had previously been reported by Need et al. (2012) as also carrying a de novo heterozygous mutation in the SMAD1 gene (601595). Functional studies of the variants and studies of patient cells were not performed. The patient had delayed development before onset of febrile seizures at age 9 months. She later developed multiple types of refractory afebrile seizures. At age 11, she was nonverbal with severe intellectual disability, autistic features, aggressive behavior, and incontinence.
Carvill, G. L., Heavin, S. B., Yendle, S. C., McMahon, J. M., O'Roak, B. J., Cook, J., Khan, A., Dorschner, M. O., Weaver, M., Calvert, S., Malone, S., Wallace, G., and 22 others. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nature Genet. 45: 825-830, 2013. [PubMed: 23708187] [Full Text: https://doi.org/10.1038/ng.2646]
de Kovel, C. G. F., Brilstra, E. H., van Kempen, M. J. A., van't Slot, R., Nijman, I. J., Afawi, Z., De Jonghe, P., Djemie, T., Guerrini, R., Hardies, K., Helbig, I., Hendrickx, R., and 13 others. Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Molec. Genet. Genomic Med. 4: 568-580, 2016. [PubMed: 27652284] [Full Text: https://doi.org/10.1002/mgg3.235]
Epi4K Consortium and Epilepsy Phenome/Genome Project. De novo mutations in epileptic encephalopathies. Nature 501: 217-221, 2013. [PubMed: 23934111] [Full Text: https://doi.org/10.1038/nature12439]
Hamdan, F. F., Srour, M., Capo-Chichi, J.-M., Daoud, H., Nassif, C., Patry, L., Massicotte, C., Ambalavanan, A., Spiegelman, D., Diallo, O., Henrion, E., Dionne-Laporte, A., Fougerat, A., Pshezhetsky, A. V., Venkateswaran, S., Rouleau, G. A., Michaud, J. L. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 10: e1004772, 2014. Note: Electronic Article. [PubMed: 25356899] [Full Text: https://doi.org/10.1371/journal.pgen.1004772]
Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., Meisler, M. H., Goldstein, D. B. Clinical application of exome sequencing in undiagnosed genetic conditions. J. Med. Genet. 49: 353-361, 2012. [PubMed: 22581936] [Full Text: https://doi.org/10.1136/jmedgenet-2012-100819]
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