Submission Details

The UNC13A gene is located on chromosome 19 at 19p13.11 and encodes unc-13 homolog A, or Munc13-1, which is one of four genes in the UNC13 homolog gene family. UNC13A was first reported in association with congenital nervous system disorder by Engel et al. (2016), who described a proband with a homozygous stop-gained variant presenting with microcephaly, cortical hyperexcitability, and myasthenia (PMID 27648472). Based on the limited number of reported cases, a distinct mode of inheritance, mechanism of disease, and phenotypic spectrum have not been determined; for this reason, the gene was curated for the broad term congenital nervous system disorder, undetermined inheritance mode. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least three variants including missense and stop-gained variants have been reported in association with a neurodevelopmental syndrome characterized by variable features of developmental delay, seizures, microcephaly, and myopathy/movement disorders (PMIDs: 27648472, 28192369, 28771251). These variants were all considered and totaled 3 points, but can't be given points in the GCI due to the unknown MOI. Biallelic loss of function has been associated with developmental delay, microcephaly, cortical hyperexcitability, hypotonia, and myopathy, whereas heterozygous gain of function has been associated with hyperkinesia, developmental delay, and autism. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. Munc13-1 is highly expressed in the brain and at the neuromuscular junction, where it localizes to presynaptic terminals and plays a critical role in synaptic transmission by regulating release site assembly, synaptic vesicle priming, activity-dependent refilling of the readily releasable vesicle pool, calcium channel proximity, and short-term synaptic plasticity (PMIDs: 17167095, 30690332). In vivo and in vitro experiments have demonstrated that variation in the UNC13A gene can alter various properties of neuronal and neuromuscular synaptic transmission and lead to muscle weakness, respiratory insufficiency, and perinatal lethality (PMIDs: 10440375, 11792326, 27648472, 28192369). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 15th, 2021 (SOP Version 8).