ORPHA: 528084;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.31 | Intellectual developmental disorder with seizures and language delay | 619000 | Autosomal dominant | 3 | SETD1B | 611055 |
A number sign (#) is used with this entry because of evidence that intellectual developmental disorder with seizures and language delay (IDDSELD) is caused by heterozygous mutation in the SETD1B gene (611055) on chromosome 12q24.
Patients with a microdeletion of chromosome 12q24 including the SETD1B gene have similar and overlapping features (Palumbo et al., 2015; Labonne et al., 2016).
Intellectual developmental disorder with seizures and language delay (IDDSELD) is characterized by global developmental delay with speech and language impairment and onset of seizures usually in the first few years of life. Seizures tend to be myoclonic, although variable types have been reported. Many patients have accompanying behavioral abnormalities, most commonly autism spectrum disorder and anxiety. Additional features, such as facial dysmorphism, tapering fingers, and pigmentary skin changes may also be observed (summary by Roston et al., 2021).
Hiraide et al. (2018) reported a 12-year-old Japanese girl (patient 1) with early-onset myoclonic seizures and impaired intellectual development. At 2 years, 9 months of age, she developed refractory myoclonic seizures with neck anteflexion and rolling of the eyes, which later evolved to frequent myoclonic absence seizures. EEG showed diffuse 2-3 Hz spike-wave discharges on a slow wave background. The seizures were eventually controlled with multiple medications, and she was seizure-free at 6 years of age. She had global developmental delay with walking at age 20 months and meaningful words at 14 months. At age 10 years, 9 months, she had mildly impaired intellectual development (IQ of 64), normal language, and autism spectrum disorder. Brain imaging was normal. An unrelated 34-year-old Japanese man (patient 2) with a similar but more severe disorder was also reported. He had onset of myoclonic seizures at age 4 years and generalized tonic seizures at age 6. EEG showed spike- and polyspike-slow wave complexes. The seizures were partially responsive to medication. This patient had global developmental delay with profoundly impaired intellectual development (IQ of 10), language delay, anxiety, and autism spectrum disorder. He also had dysmorphic features, including square face, thick eyebrows, downslanting palpebral fissures, flat occiput, full cheeks, full lower lip, and mildly tapered fingers. Brain imaging was normal. Patient 2 developed sigmoid adenocarcinoma at age 30.
Den et al. (2019) reported a Japanese girl with IDDSELD. At 2 years of age, she developed jerks associated with fever, followed by daily myoclonic seizures with EEG abnormalities, including diffuse spike and slow wave complexes with a background activity of occipital 5-6 Hz theta waves. She had developmental delay, language delay, and autistic behavior. Brain imaging was normal, and she did not have dysmorphic features.
Krzyzewska et al. (2019) reported 3 unrelated patients (patients 1, 2, and 5), aged 7 to 16 years, with IDDSELD. They were able to walk without support, but had impaired intellectual development and language delay. Two had documented seizures (the information was not available for the third patient), and 1 had autism. Two patients had dysmorphic features, including upslanting palpebral fissures, proptosis, hypertelorism, sunken eyes, short palpebral fissures, thick eyebrows, full cheeks, cleft lip/palate, and oligodontia.
Roston et al. (2021) reported 4 unrelated patients, ranging in age from 3.5 to 19 years, with IDDSELD. The patients had global developmental delay with mildly delayed walking, mildly to moderately impaired intellectual development, and speech impairment. Three patients had onset of seizures between 2 and 3 years of age, whereas 1 had onset of seizures at age 12. Seizure types included myoclonus, eyelid myoclonus, facial twitching, and absence and generalized tonic-clonic seizures. EEG abnormalities were variable; the seizures were difficult to control in some patients. Two patients had autism and 1 had attention deficit/hyperactivity disorder. Growth parameters and brain imaging were essentially normal. Other more variable features included joint laxity, lumbar lordosis, inguinal hernia, eczema or pigmentary skin abnormalities, and periodic shaking of the hands. One patient had subtle dysmorphic features, including downslanting palpebral fissures, small ears, midface hypoplasia, small nose, smooth philtrum, full cheeks, thin upper lip, fifth finger clinodactyly, and persistent fingertip pads.
Weerts et al. (2021) reported clinical features in 28 patients with IDDSELD, including 17 males and 11 females, with pathogenic or likely pathogenic mutations in the SETD1B gene. Features included seizures (20/28), which were generalized at onset in 16 patients; developmental delay (26/28); intellectual disability (21/25); autism spectrum disorder (18/28); and sleep disturbances (6/25). Dysmorphic facial features seen in the cohort included a high anterior hairline, thick arched or straight eyebrows, deep-set eyes, thin lips, and a prominent nose.
The heterozygous mutations in the SETD1B gene that were identified in patients with IDDSELD by Hiraide et al. (2018) occurred de novo.
In 2 unrelated Japanese patients with IDDSELD, Hiraide et al. (2018) identified de novo heterozygous missense mutations in the SETD1B gene (R1842W, 611055.0001; R1859C, 611055.0002). The mutations, which were found by trio-based whole-exome sequencing and confirmed by Sanger sequencing, were not present in several public databases, including dbSNP (build 137), 1000 Genomes Project, and ExAC. Functional studies of the variants and studies of patient cells were not performed. The patients were part of a cohort of 337 individuals with childhood-onset epilepsy who underwent trio-based whole-exome sequencing. In addition to the mutation in the SETD1B gene, patient 2, who had a more severe phenotype, carried additional variants in 4 other genes that may have contributed to the disorder. These included a de novo A9V variant in the KCNH7 gene (608169), a hemizygous L185I variant in the CNKSR2 gene (300724), a Y80C variant in the TBX22 gene (300307), and a D740E variant in the PCDH19 gene (300460).
In a Japanese girl with IDDSELD, Den et al. (2019) identified a de novo heterozygous frameshift in the last exon of the SETD1B gene (611055.0003) that was demonstrated to escape nonsense-mediated mRNA decay and predicted to produce a truncated protein. Additional functional studies were not performed, but the findings suggested a possible gain-of-function effect. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing; it was not present in multiple public databases, including gnomAD.
In 3 unrelated patients with IDDSELD, Krzyzewska et al. (2019) identified heterozygous mutations in the SETD1B gene (611055.0001-611055.0002; R1301X, 611055.0004). Two of the mutations occurred de novo; the inheritance pattern in the third patient was unknown. The mutations were detected by whole-exome sequencing, and some of the patients were gathered through the GeneMatcher program. Using differential analysis to study patient DNA, Krzyzewska et al. (2019) found a shift of the genomewide methylation status toward hypermethylation compared to controls. This 'episignature' was unique to patients with SETD1B mutations when compared to patients with other neurodevelopmental disorders associated with methylation changes. The authors postulated a loss-of-function effect of the mutations.
Weerts et al. (2021) identified mutations in the SETD1B gene in 36 patients with neurodevelopmental disorders. Thirty-two patients had heterozygous mutations, 28 of which were shown to be de novo, 1 was inherited from an affected parent, and 1 was inherited from an unaffected parent. Of the heterozygous mutations, 14 were considered to be pathogenic (see, e.g., 611055.0008-611055.0012) and 10 were considered to be likely pathogenic. Four patients (patients 3, 4, 11, and 12) from 3 families had biallelic variants of unknown significance in the SETD1B gene, which were inherited from unaffected carrier parents.
Den, K., Kato, M., Yamaguchi, T., Miyatake, S., Takata, A., Mizuguchi, T., Miyake, N., Mitsuhashi, S. Matsumoto, N. A novel de novo frameshift variant in SETD1B causes epilepsy. J. Hum. Genet. 64: 821-827, 2019. [PubMed: 31110234] [Full Text: https://doi.org/10.1038/s10038-019-0617-1]
Hiraide, T., Nakashima, M., Yamoto, K., Fukuda, T., Kato, M., Ikeda, H., Sugie, Y., Aoto, K., Kaname, T., Nakabayashi, K., Ogata, T., Matsumoto, N., Saitsu, H. De novo variants in SETD are associated with intellectual disability, epilepsy and autism. Hum. Genet. 137: 95-104, 2018. [PubMed: 29322246] [Full Text: https://doi.org/10.1007/s00439-017-1863-y]
Krzyzewska, I. M., Maas, S. M., Hennerman, P., Lip, K., Venema, A., Baranano, K., Chassevent, A., Aref-Eshghi, E., van Essen, A. J., Fukuda, T., Ideda, H., Jacquemont, M., and 15 others. A genome-wide DNA methylation signature for SETD1B-related syndrome. Clin. Epigenet. 11: 156, 2019. Note: Electronic Article. [PubMed: 31685013] [Full Text: https://doi.org/10.1186/s13148-019-0749-3]
Labonne, J. D. J., Lee, K.-H., Iwase, S., Kong, I.-K., Diamond, M. P., Layman, L. C., Kim, C.-H., Kim, H.-G. An atypical 12q24.31 microdeletion implicates six genes including a histone demethylase KDM2B and a histone methyltransferase SETD1B in syndromic intellectual disability. Hum. Genet. 135: 757-771, 2016. [PubMed: 27106595] [Full Text: https://doi.org/10.1007/s00439-016-1668-4]
Palumbo, O., Palumbo, P., Delvecchio, M., Palladino, T., Stallone, R., Crisetti, M., Zelante, L., Carella, M. Microdeletion of 12q24.31: report of a girl with intellectual disability, stereotypies, seizures and facial dysmorphisms. Am. J. Med. Genet. 167A: 438-444, 2015. [PubMed: 25428890] [Full Text: https://doi.org/10.1002/ajmg.a.36872]
Roston, A., Evans, D., Gill, H., McKinnon, M., Isidor, B., Cogne, B., Mwenifumbo, J., van Karnebeek, C., An, J., Jones, S. J. M., Farrer, M., Demos, M., Connelly, M., Gibson, W. T., CAUSES Study, EPGEN Study. SETD1B-associated neurodevelopmental disorder. J. Med. Genet. 58: 196-204, 2021. Note: Erratum: J. Med. Genet. 17Aug, 2022. Advance Electronic Publication. [PubMed: 32546566] [Full Text: https://doi.org/10.1136/jmedgenet-2019-106756]
Weerts, M. J. A., Lanko, K., Guzman-Vega, F. J., Jackson, A., Ramakrishnan, R., Cardona-Londono, K. J., Pena-Guerra, K. A., van Bever, Y., van Paassen, B. W., Kievit, A., van Slegtenhorst, M., Allen, N. M., and 86 others. Delineating the molecular and phenotypic spectrum of the SETD1B-related syndrome. Genet. Med. 23: 2122-2137, 2021. [PubMed: 34345025] [Full Text: https://doi.org/10.1038/s41436-021-01246-2]