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Abstract: Background: Multiple variants in SNCA, encoding alpha‐synuclein, a main component of Lewy bodies, are implicated in Parkinson's disease. Methods: We searched for cis‐acting SNCA variants using allelic mRNA ratios in human brain tissues. In a SNCA 3′UTR (2,520 bp) luciferase reporter gene assay, translation in SH‐SY5Y cells in the presence of the rs17016074 G/A alleles was measured. To assess clinical impact, we queried neurocognitive genome‐wide association studies. Results: Allelic ratios deviated up to twofold, measured at a marker SNP in the middle of a long 3′ untranslated region (3′UTR), but not at a marker at its start, suggesting regulation of 3′UTR processing. 3′UTR SNP rs17016074 G/A, minor allele frequency (MAF) <1% in Caucasians, 13% in Africans, strongly associates with large allelic mRNA expression imbalance (AEI), resulting in reduced expression of long 3′UTR isoforms. A second 3′UTR SNP (rs356165) associates with moderate AEI and enhances SNCA mRNA expression. The rs17016074 A allele reduces overall 3′UTR expression in luciferase reporter gene assays but supports more efficient translation, resolving previous contradictory results. We failed to detect significant genome‐wide associations for rs17016074, possibly a result of low MAF in Caucasians or its absence from most genotyping panels. In the “Genome Wide Association Study of Yoruba in Nigeria,” rs356165 was associated with reduced memory performance. Conclusions: Here, we identify two cis‐acting regulatory variants affecting SNCA mRNA expression, measured by allelic ratios in the 3′UTR. The rs17016074 minor A allele is associated with higher expression of luciferase protein activity. Resolving the genetic influence of SNCA polymorphisms requires study of the interactions between multiple regulatory variants with distinct frequencies among populations. [ABSTRACT FROM AUTHOR]

Purpose While chromosomal regions of homozygosity (ROH) may implicate genes in known recessive disorders, their correlation to disease pathogenicity remains unclear. ROH around the centromere of the X chromosome (pericentromeric, pROH) is regarded as benign, although this has not been empirically demonstrated. Methods We examined microarray results from 122 female individuals harboring ROH bordering the X centromere. Results Consecutive ROH was most frequently observed for regions Xp11.23 to Xp11.21 and Xq11.1 to Xq12, with an average total size of 16.5 Mb. X chromosome pROH was unlikely related to phenotype in 41% (50/122) of cases due to other explanations: likely pathogenic deletion/duplication (17%, 21/122), apparently unaffected female (7%, 8/122), other clinical explanation (7%, 9/122), or consanguinity (10%, 12/122). Of the remaining cases with pROH as the only finding, four genes were associated with recessive disorders that overlapped one or more clinical features reported in our probands ( KDM5C , FGD1 , ZC4H2 , and LAS1L ). X chromosome pROH observed in our cohort overlapped with previously reported regions. Conclusions pROH on the X chromosome are commonly observed in both affected individuals with alternate causes of disease as well as in unaffected individuals, suggesting that X chromosome pROH has no clinically significant effect on phenotype. [ABSTRACT FROM AUTHOR]

Frequent non-pathogenic genetic variants may act as moderators of phenotypic severity for complex disorders such as autism spectrum disorder (ASD). We previously identified polymorphisms affecting mRNA expression of candidate genes, including tryptophan hydroxylase 2 (TPH2), dopamine beta hydroxylase (DBH), and dopamine transporter (DAT, SLC6A3). We compare genotypes and (1) clinical response to atomoxetine, (2) scores from the Autism Diagnostic Interview-Revised (ADI-R), and (3) severity of Attention Deficit Hyperactivity Disorder (ADHD) symptoms in a cohort of patients with ASD from multiple study sites. There was no association between CYP2D6 metabolizer status and atomoxetine response. TPH2 rs7305115 genotype was associated with ADI-R Restrictive/Repetitive Behavior score (p = 0.03). DBH rs1611115 genotype was associated with ADI-R Social score (p = 0.002), and Restrictive/Repetitive Behavior score (p = 0.04). The DAT intron 8 5/6 repeat was associated with ADHD symptoms (ABC Hyperactivity p = 0.01 and SNAP ADHD p = 0.03), replicating a previous finding. We find associations between ASD phenotypes and regulatory variants in catecholamine biosynthesis genes. This work may help guide future genetics studies related to ASD. [ABSTRACT FROM AUTHOR]

There is compelling evidence that autoreactive CD8+Tcells play a central role in precipitating the development of autoimmune diabetes in non-obese diabetic (NOD) mice, but the underlying mechanisms remain unclear. Given that ITGAE (CD103) recognizes an isletrestricted ligand (E-cadherin), we postulated that its expression is required for initiation of disease. We herein use a mouse model of autoimmune diabetes (NOD/ShiLt mice) to test this hypothesis. We demonstrate that ITGAE is expressed by a discrete subset of CD8+ Tcells that infiltrate pancreatic islets before the development of diabetes. Moreover, we demonstrate that development of diabetes in /igae-deficient NOD mice is significantly delayed at early but not late time points, indicating that ITGAE is preferentially involved in early diabetes development. To rule out a potential contribution by closely linked loci to this delay, we treated WT NOD mice beginning at 2 weeks of age through 5 weeks of age with a depleting anti-ITGAE mAb and found a decreased incidence of diabetes following anti-ITGAE mAb treatment compared with mice that received isotype control mAbs or non-depleting mAbsto ITGAE. Moreover, a histological examination of the pancreas of treated mice revealed that NOD mice treated with a depleting mAb were resistant to immune destruction. These results indicate that ITGAE + cells play a key role in the development of autoimmune diabetes and are consistent with the hypothesis that ITGAE+ CD8+T effectors initiate the disease process. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the IQSEC2 gene including nonsense, frameshift, splice-alterations, deletions, and missense changes have been identified in individuals with X-linked mental retardation. Although highly variable, clinical features may include hypotonia, moderate to severe delayed psychomotor development, intellectual disability, speech deficits, refractory seizures, autistic features, and stereotypical movements. Females with de novo variants have been described with classical features. In contrast, the phenotype in carrier females identified through an affected male may range from asymptomatic to mild intellectual disability. We present male (N = 2) and female (N = 3) probands ascertained via diagnostic exome sequencing with distinct variant types in the IQSEC2 gene encompassing a spectrum of phenotypic severity with patient sex, variant type and inheritance hypothesized to drive disease penetrance and expressivity. All of these patients demonstrated epilepsy, global developmental delays, intellectual disability, and constipation. Our data support that de novo , truncating variants correlate with severe disease in both female and male patients harboring an IQSEC2 alteration. Missense variants in male and female patients may account for a milder disease overall, with more severe symptoms in males than females. We also present the first confirmed case of parental mosaicism, which has implications regarding counseling for recurrence risk. These data further delineate a genotype-phenotype correlation of IQSEC2 variation. [ABSTRACT FROM AUTHOR]

Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a “C” or a “T” at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice. [ABSTRACT FROM AUTHOR]