| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p22.3 | Marbach-Schaaf neurodevelopmental syndrome | 619680 | Autosomal dominant | 3 | PRKAR1B | 176911 |
A number sign (#) is used with this entry because of evidence that Marbach-Schaaf neurodevelopmental syndrom (MASNS) is caused by heterozygous mutation in the PRKAR1B gene (176911) on chromosome 7p22.
Marbach-Schaaf neurodevelopmental syndrom (MASNS) is characterized by global developmental delay with speech delay and behavioral abnormalities, including autism spectrum disorder and ADHD. Affected individuals also show movement disorders, such as dyspraxia and apraxia. More variable features include high pain tolerance, sleep disturbances, and variable nonspecific dysmorphic features (summary by Marbach et al., 2021).
Marbach et al. (2021) reported 6 unrelated patients, ranging from 3 to 16 years of age, with a similar neurodevelopmental disorder characterized by global developmental delay with speech delay, behavioral abnormalities, hypotonia, and movement disorders, including dyspraxia, apraxia, and clumsiness. One patient had tremor and dystonia. Two patients showed regression of language skills, including 1 who became nonverbal by age 7. All patients were diagnosed with autism spectrum disorder. Four had ADHD and several had aggressive behavior or arm flapping. More variable features included high pain tolerance, sleep disturbances or sleep apnea, and hyperphagia resulting in increased BMI. One patient had seizures; the patient's mother also had a seizure disorder. A few patients had nonspecific dysmorphic features, including upslanting palpebral fissures, epicanthal folds, flat nasal bridge, and downturned mouth.
The heterozygous mutations in the PRKAR1B gene that were identified in patients with MASNS by Marbach et al. (2021) occurred de novo.
In 6 unrelated patients with MASNS, Marbach et al. (2021) identified heterozygous missense mutations in the PRKAR1B gene (176911.0002-176911.0004). The mutations, which were found by exome sequencing, occurred de novo in 5 patients; parental DNA from the sixth patient was not available. Four patients carried the same mutation (R335W; 176911.0002), suggesting a potential mutational hotspot, and all mutations were absent from the gnomAD database. In vitro functional expression studies in HEK293 cells transfected with the mutations showed that all caused significantly decreased basal PKA enzymatic activity compared to controls, consistent with a loss of function.
Marbach, F., Stoyanov, G., Erger, F., Stratakis, C. A., Settas, N., London, E., Rosenfeld, J. A., Torti, E., Haldeman-Englert, C., Sklirou, E., Kessler, E., Ceulemans, S., and 18 others. Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain. Genet. Med. 23: 1465-1473, 2021. [PubMed: 33833410] [Full Text: https://doi.org/10.1038/s41436-021-01152-7]