Alternative titles; symbols
ORPHA: 36387; DO: 0111305;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 5q14.3 | ?Febrile seizures, familial, 4 | 604352 | Autosomal dominant | 3 | ADGRV1 | 602851 |
A number sign (#) is used with this entry because of evidence that familial febrile seizures-4 (FEB4) is caused by a heterozygous mutation in the ADGRV1 gene (602851) on chromosome 5q14. One such family has been reported.
For a phenotypic description and a discussion of genetic heterogeneity of familial febrile seizures, see FEB1 (121210).
Han et al. (2020) reported a 5-year-old girl who had recurrent febrile and afebrile seizures between 20 and 36 months of age. She received no antiseizure medication, and no seizures occurred after 3 years of age. She had no developmental delay. Her 35-year-old mother reportedly experienced 5 episodes of simple febrile seizures and 2 episodes of unprovoked seizures before age 5 years.
Nakayama et al. (2002) reported a Japanese family (FS17) in which the proband and her brother had febrile seizures and mutation in the ADGRV1 gene, encoding MASS1. The proband was a 12-year-old girl who had a febrile generalized tonic-clonic seizure lasting 5 minutes at age 2 years. At 3 years of age, she also had an afebrile generalized clonic seizure with left side dominance lasting less than 1 minute. Brain magnetic resonance imaging showed no abnormal findings, and electroencephalograph showed sharp waves in the right central area that disappeared by the time she was 10 years of age. Her 11-year-old brother had 2 febrile generalized tonic-clonic seizures, once at age 6 years and once at age 7 years. His electroencephalograph showed single spike and wave discharges in the right hemisphere that disappeared by the time he was 7 years old. Both affected children had normal mental and motor development. The father carried the mutation and was reported to be unaffected; the father's sister had recurrent febrile seizures during childhood but declined to be examined.
The transmission pattern of FEB4 in family FS17 reported by Nakayama et al. (2002) was consistent with autosomal dominant inheritance.
Nakayama et al. (2000) conducted a genomewide linkage study for febrile seizures in 1 large family, with subsequent confirmation of linkage in 39 nuclear families. Significant linkage was found at D5S644 by multipoint nonparametric analysis. Significant linkage disequilibrium with febrile seizures was observed at markers D5S644, D5S652, and D5S2079 in 47 families by transmission disequilibrium tests. These findings indicated that there is a gene on chromosome 5q14-q15, which the authors referred to as FEB4, that confers susceptibility to febrile seizures.
Because mutation in the mouse Mass1 gene was found to be the cause of audiogenic seizure susceptibility in the Frings mouse strain, Nakayama et al. (2002) screened for mutations in the GPR98, or MASS1 (ADGRV1), gene in individuals from 48 families with familial febrile seizures showing suggestive evidence of linkage to 5q14. They identified 25 DNA alterations. None of 9 missense polymorphic alleles was significantly associated with febrile seizures; however, a nonsense mutation (S2652X; 602851.0001) causing a deletion of the C-terminal 126 amino acid residues was identified in 1 family with febrile and afebrile seizures. The results suggested that a loss-of-function mutation in MASS1 may be responsible for the seizure phenotype, but that mutation in the MASS1 gene is not likely to be a contributing factor in most families with febrile seizures.
In a proband and her mother with febrile seizures, Han et al. (2020) identified a heterozygous missense mutation in the ADGRV1 gene (NM_032119.3, c.2039A-G, D180G, rs547076322). The mutation was identified by targeted exome sequencing and confirmed by Sanger sequencing. The variant had an allele frequency of 2.8 x 10(-5) in the gnomAD database. No functional studies were performed. The authors concluded that the mutation may be a cause of FEB4.
Deprez et al. (2006) performed a 10-cM density genomewide scan in a multigenerational family with febrile seizures and epilepsy and attained a maximal multipoint lod score of 3.12 with markers on 5q14.3-q23.1. This candidate region overlapped with the FEB4 locus identified in the Japanese population, in which MASS1 was proposed as the disease gene (Nakayama et al., 2002). In mutation analysis of the exons and exon-intron boundaries of MASS1 in their family, Deprez et al. (2006) found no disease-causing mutation. It may be that another gene within or near the FEB4 locus is responsible for seizures in this family. The family resided in Flanders, the Dutch-speaking region of Belgium.
Deprez, L., Claes, L. R. F., Claeys, K. G., Audenaert, D., Van Dyck, T., Goossens, D., Van Paesschen, W., Del-Favero, J., Van Broeckhoven, C., De Jonghe, P. Genome-wide linkage of febrile seizures and epilepsy to the FEB4 locus at 5q14.3-q23.1 and no MASS1 mutation. Hum. Genet. 118: 618-625, 2006. [PubMed: 16273391] [Full Text: https://doi.org/10.1007/s00439-005-0077-x]
Han, J. Y., Lee, H. J., Lee, Y.-M., Park, J. Identification of missense ADGRV1 mutation as a candidate genetic cause of familial febrile seizure 4. Children 7: 144, 2020. Note: Electronic Article. [PubMed: 32962041] [Full Text: https://doi.org/10.3390/children7090144]
Nakayama, J., Fu, Y.-H., Clark, A. M., Nakahara, S., Hamano, K., Iwasaki, N., Matsui, A., Arinami, T., Ptacek, L. J. A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann. Neurol. 52: 654-657, 2002. [PubMed: 12402266] [Full Text: https://doi.org/10.1002/ana.10347]
Nakayama, J., Hamano, K., Iwasaki, N., Nakahara, S., Horigome, Y., Saitoh, H., Aoki, T., Maki, T., Kikuchi, M., Migita, T., Ohto, T., Yokouchi, Y., Tanaka, R., Hasegawa, M., Matsui, A., Hamaguchi, H., Arinami, T. Significant evidence for linkage of febrile seizures to chromosome 5q14-q15. Hum. Molec. Genet. 9: 87-91, 2000. [PubMed: 10587582] [Full Text: https://doi.org/10.1093/hmg/9.1.87]