Alternative titles; symbols
ORPHA: 488613; DO: 0070072;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p36.33 | Intellectual developmental disorder, autosomal dominant 42 | 616973 | Autosomal dominant | 3 | GNB1 | 139380 |
A number sign (#) is used with this entry because of evidence that autosomal dominant intellectual developmental disorder-42 (MRD42) is caused by heterozygous mutation in the GNB1 gene (139380) on chromosome 1p36.
Autosomal dominant intellectual developmental disorder-42 (MRD42) is characterized by global developmental delay and impaired intellectual development. More variable features include hypotonia, often later associated with limb hypertonia, seizures of various types, and poor overall growth. Strabismus, cortical visual impairment, and autistic features may also be present (summary by Petrovski et al., 2016).
Petrovski et al. (2016) reported 13 unrelated individuals, ranging in age from 13 months to 20 years, with global developmental delay. Additional common, but somewhat variable, features included hypotonia (11 patients), seizures (10 patients), and poor overall growth without microcephaly. Hypotonia varied in severity: 3 patients were unable to ambulate and 4 developed limb hypertonia. Seizures types included focal, generalized, myoclonic, atonic, tonic, absence, and complex partial, and the age at seizure onset ranged from infancy to 11 years. EEG patterns were variable, with generalized slowing and multifocal spikes; some patients showed hypsarrhythmia. Eight patients had variable ophthalmologic abnormalities, including strabismus, nystagmus, slow ocular pursuit, and cortical visual impairment. A few patients had autism spectrum disorder or attention deficit-hyperactivity disorder, and 2 had hydronephrosis. Some had mild dysmorphic features, such as cleft palate, but there was no recognizable gestalt. Brain imaging was normal in most patients, but 1 patient had polymicrogyria and delayed myelination.
Lohmann et al. (2017) reported 16 patients, aged 1 to 12 years, of whom 15 had global developmental delay, 5 had growth delay, 7 had hypotonia, 3 had craniosynostosis, 13 had impaired intellectual development, and 9 had seizures. Brain imaging findings included cerebellar hypoplasia in 3 patients and abnormal myelination in 6. Seven patients had nystagmus and 4 patients had ophthalmoplegia. Movement disorders included ataxia in 5 patients, chorea in 1 patient, and dystonia in 1 patient.
Hemati et al. (2018) reported 18 patients, aged 2 to 16 years, of whom all had moderate to severe neurodevelopmental deficits and 17 had motor delay. All of the patients had speech delay, and 13 were nonverbal. Brain MRI findings in the cohort that were observed in at least 2 patients included abnormal or delayed myelination, abnormal corpus callosum, cerebral volume loss, and/or ventriculomegaly. Six of the patients had epilepsy. Four of 8 males had genitourinary anomalies, including 3 with undescended tests and 1 with bifid scrotum and duplicated collecting system. Eleven of the patients had gastrointestinal abnormalities including recurrent constipation and cyclical vomiting. Cutaneous mastocytosis was seen in 3 patients. One patient had a ventricular septal defect and one had a duplicated superior vena cava.
Szczaluba et al. (2018) reported a patient who had severely delayed gross and fine motor skills within the first year of life. A neurologic assessment revealed muscular hypotonia and upper limb choreoathetosis. Features of cutaneous mastocytosis presented at the end of the first year of life, and urticaria pigmentosa was confirmed by skin biopsy. At age 4 years, she had global developmental delay and generalized hypotonia. She also had bilateral severe vesicoureteral reflux resulting in unilateral nephrectomy.
In 13 unrelated patients with MRD42, Petrovski et al. (2016) identified 9 different de novo heterozygous missense mutations in the GNB1 gene (see, e.g., 139380.0001-139380.0005). The mutations were identified by exome sequencing and confirmed by Sanger sequencing. The patients were ascertained from a cohort of 5,855 individuals with a presumed genetic disorder of unknown cause. Functional studies and studies of patient cells were not performed by Petrovski et al. (2016). However, Petrovski et al. (2016) noted that Yoda et al. (2015) had identified somatic mutations in the GNB1 gene that were associated with hematologic transformation. Functional studies of 3 of the mutations (D76G, 139380.0001; I80T, 139380.0002; I80N, 139380.0003) that were also identified as germline mutations in the patients reported by Petrovski et al. (2016) had reduced binding to almost all G-alpha subunits and/or conferred cytokine-independent growth and activation of canonical G protein downstream signaling through disruption of the G-alpha/G-beta/G-gamma interaction interface. The mutations resulted in activation of the PI3K-AKT-mTOR and MAPK pathways, consistent with a gain of function.
In 16 patients with MRD42, Lohmann et al. (2017) identified 14 mutations in the GNB1 gene, including 2 frameshift mutations (139380.0007 and 139380.0008), 2 splicing mutations (139380.0006 and 139380.0009), and 10 missense mutations (see, e.g., 139380.0010). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing; 1 mutation was inherited from a parent, 10 were de novo, and the inheritance of 3 mutations could not be determined due to lack of parental samples. Using a cell-based bioluminescence resonance energy transfer (BRET) assay, Lohmann et al. (2017) demonstrated that 7 of the missense mutations resulted in deficits in receptor-driven G protein activation.
Hemati et al. (2018) reported 18 patients with MRD42 and de novo heterozygous mutations in the GNB1 gene. Twelve patients had heterozygosity for previously identified mutations, including 8 patients with I80T (139380.0002). One of the mutations (C114Y; 13980.0011) was identified in a somatic mosaic state. All of the mutations were found by trio whole-exome sequencing.
In a 4-year-old girl with MRD42 616973, Szczaluba et al. (2018) identified a de novo heterozygous missense mutation (G77V; 139380.0012) in the GNB1 gene. The mutation was found by trio whole-exome sequencing and confirmed by Sanger sequencing.
Lansdon and Saunders (2021) noted that a genotype-phenotype correlation has been proposed between the most commonly mutated residue in the GNB1 gene, I80, and cutaneous mastocytosis, severe axial hypotonia or hypotonic quadriplegia, and dystonia. They reported that 4 of 5 patients with MRD42 and an L95P mutation in the GNB1 gene had cleft palate. Statistical analysis of patients with clefting versus those without who had L95P compared to all other GNB1 variants combined revealed an association with cleft palate (p = 0.00013).
Hemati, P., Revah-Politi, A., Bassan, H., Petrovski, S., Bilancia, C. G., Ramsey, K., Griffin, N. G., Bier, L., Cho, M. T., Rosello, M., Lynch, S. A., Colombo, S., and 42 others. Refining the phenotype associated with GNB1 mutations: clinical data on 18 newly identified patients and review of the literature. Am. J. Med. Genet. 176A: 2259-2275, 2018. [PubMed: 30194818] [Full Text: https://doi.org/10.1002/ajmg.a.40472]
Lansdon, L. A., Saunders, C. J. Genotype-phenotype correlation in GNB1-related neurodevelopmental disorder: potential association of p.Leu95Pro with cleft palate. Am. J. Med. Genet. 185A: 1341-1343, 2021. [PubMed: 33427398] [Full Text: https://doi.org/10.1002/ajmg.a.62080]
Lohmann, K., Masuho, I., Patil, D. N., Baumann, H., Hebert, E., Steinrucke, S., Trujillano, D., Skamangas, N. K., Dobricic, V., Huning, I., Gillessen-Kaesbach, G., Westenberger, A., Savic-Pavicevic, D., Munchau, A., Oprea, G., Klein, C., Rolfs, A., Martemyanov, K. A. Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans. Hum. Molec. Genet. 26: 1078-1086, 2017. [PubMed: 28087732] [Full Text: https://doi.org/10.1093/hmg/ddx018]
Petrovski, S., Kury, S., Myers, C. T., Anyane-Yeboa, K., Cogne, B., Bialer, M., Xia, F., Hemati, P., Riviello, J., Mehaffey, M., Besnard, T., Becraft, E., and 35 others. Germline de novo mutations in GNB1 cause severe neurodevelopmental disability, hypotonia, and seizures. Am. J. Hum. Genet. 98: 1001-1010, 2016. [PubMed: 27108799] [Full Text: https://doi.org/10.1016/j.ajhg.2016.03.011]
Szczaluba, K., Biernacka, A., Szymanska, K., Gasperowicz, P., Kosinska, J., Rydzanicz, M., Ploski, R. Novel GNB1 de novo mutation in a patient with neurodevelopmental disorder and cutaneous mastocytosis: clinical report and literature review. Europ. J. Med. Genet. 61: 157-160, 2018. [PubMed: 29174093] [Full Text: https://doi.org/10.1016/j.ejmg.2017.11.010]
Yoda, A., Adelmant, G., Tamburini, J., Chapuy, B., Shindoh, N., Yoda, Y., Weigert, O., Kopp, N., Wu, S.-C., Kim, S. S., Liu, H., Tivey, T., and 17 others. Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance. Nature Med. 21: 71-75, 2015. [PubMed: 25485910] [Full Text: https://doi.org/10.1038/nm.3751]