Population Prevalence of Deleterious <i>SGCE</i> Variants

Abstract

Background: Myoclonus-Dystonia (M-D) is a pleiotropic neuropsychiatric disorder of variable penetrance. Pathogenic variants in SGCE , a maternally imprinted gene, are the most frequent known genetic cause of M-D. The population prevalence of SGCE -linked M-D is unknown, the pathogenicity of SGCE variants identified in patients with M-D may be indeterminant, and SGCE variants predicted to be deleterious by in silico analysis may appear in patients undergoing whole-exome or whole-genome sequencing for seemingly unrelated disorders. The Genome Aggregation Database (gnomAD) v2 provides variant data on 125,748 exomes and 15,708 genomes from unrelated individuals sequenced as part of various disease-specific and population genetic studies. Methods: SGCE variants included in the gnomAD v2 dataset were analyzed with Combined Annotation Dependent Depletion (CADD), and database for nonsynonymous single nucleotide polymorphisms’ functional predictions (dbNSFP). We determined the frequency of annotated SGCE variants, ranked by scores of deleteriousness, within the gnomAD v2 dataset. Deleteriousness scores were compared to a subset of published disease associated SGCE pathogenic variants. Results: Within gnomAD v2, there were 56, 408, and 1250 alleles harboring SGCE variants with CADD scores greater than 30, 25, and 20, respectively. We estimate that approximately 1/348 individuals in the United States population harbors an SGCE variant with a CADD score ≥ 25. Discussion: SGCE M-D may be underdiagnosed due to pleiotropy, mild phenotypes, variable penetrance, and impaired access to genetic testing. Due to the high population prevalence of deleterious SGCE variants, caution should be used when asserting pathogenicity without co-segregation analyses and expert neurological examination of phenotypes within pedigrees. Highlights In silico analyses of a large population database of genetic variants revealed that over 0.2% of individuals in the United States harbor a highly deleterious SGCE variant. This finding suggests that M-D and minor phenotypic variants such as mild isolated myoclonus may be underdiagnosed.

Detection of a new deleterious SGCE gene variant in Moroccan family with inherited myoclonus–dystonia

“…In many publications, it has been reported that M‐D has been linked to all types of variants including single‐exonic deletions, interstitial deletions, indels, in‐frame deletions, nonsynonymous single‐nucleotide missense, and splice, and the vast majority of indels lead to frameshifts and stops. Le Doux 25 has compiled all variants reported and ranked them by scores of deleteriousness, within the gnomAD v2 dataset. The new mutation c.662G> A has not been reported before, but the same position has been found, causing Gly‐to‐Asp protein change, 26 and was the unique missense mutation found in this cohort among thirteen different pathogenic variants (including nonsense mutations and deletions).…”

“…This missense mutation is added to other six missense variants reported in Ref. [25] in which the CADD_ PHRED scores range from 23.8 to 35 and are predicted to cause disease by MetaLR, MetaSVM, and MutationTaster. REVEL_rankscores ranged from 0.852 (p. Thr36Arg) to 0.997 (p. Tyr115Cys).…”

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

“…Remarkably, SGCE, CACNA1B, and GRIN2A are well-known for causing Myoclonus-Dystonia (M-D), a hyperkinetic movement disorder, which is similar to tics, a diagnostic feature of PANDAS. SGCE, in fact, is the most commonly mutated gene in M-D, with more than one-third of cases having truncating mutations in exon 3, which contains the del150Iso in-frame mutation found in case 10 104–106 . Interestingly, patients with myoclonus caused by SGCE mutations frequently have co-morbid psychiatric symptoms, including depression, anxiety, bipolar disorder, phobias, alcoholism, and OCD 106 , symptoms that overlap with PANS.…”