The genetics of colored sequence synesthesia: Evidence of linkage to chromosome 16q and genetic heterogeneity for the condition

Synesthesia is a perceptual condition in which normal sensory stimulation can trigger anomalous sensory experiences. For example, synesthetes may experience colors in response to sounds, tastes in response to words, or smells in response to touch. We here focus on colored sequence synesthesia, in which color experiences are triggered by learned ordinal sequences such as letters, numbers, weekdays and months. Although synesthesia has been noted in the scientific literature for over a century, it is understood only at the level of the phenomenology, and not at the molecular and neural levels. We have performed a linkage analysis to identify the first genetic loci responsible for the increased neural crosstalk underlying colored sequence synesthesia. Our analysis has identified a 23 MB region on chromosome 16 as a putative locus for the trait. Our data provide the first step in understanding neural crosstalk from its molecular basis to its behavioral consequences, opening a new inroad into the understanding of the multisensory brain

A Novel ESRRB Deletion Is a Rare Cause of Autosomal Recessive Nonsyndromic Hearing Impairment among Pakistani Families

Mutations in the estrogen-related receptor beta (ESRRB) gene is the underlying cause of autosomal recessive nonsyndromic hearing impairment (ARNSHI) due to the DFNB35 locus which maps to 14q24.3. A genome scan of a large consanguineous Pakistani pedigree with ARNSHI established linkage with a maximum multipoint LOD score of 4.2 to the 14q24 region and the region of homozygosity contained the ESRRB gene. Sequencing of the ESRRB gene using DNA samples from hearing-impaired family members uncovered a novel three-nucleotide deletion c.1018_1020delGAG (p.Glu340del). The deletion segregates with hearing impairment in the pedigree and was not observed in 500 control chromosomes. The deletion of glutamic acid residue occurs in the ligand-binding domain of ESRRB protein. It is expected that the deletion affects the ligand-binding activity of the domain in ESRRB, which leads to the ARNSHI

Autosomal recessive nonsyndromic hearing impairment in two Finnish families due to the population enriched CABP2 c.637+1G > T variant

Background: The genetic architecture of hearing impairment in Finland is largely unknown. Here, we investigated two Finnish families with autosomal recessive nonsyndromic symmetrical moderate-to-severe hearing impairment. Methods: Exome and custom capture next-generation sequencing were used to detect the underlying cause of hearing impairment. Results: In both Finnish families, we identified a homozygous pathogenic splice site variant c.637+1G>T in CAPB2 that is known to cause autosomal recessive nonsyndromic hearing impairment. Four CABP2 variants have been reported to underlie autosomal recessive nonsyndromic hearing impairment in eight families from Iran, Turkey, Pakistan, Italy, and Denmark. Of these variants, the pathogenic splice site variant c.637+1G>T is the most prevalent. The c.637+1G>T variant is enriched in the Finnish population, which has undergone multiple bottlenecks that can lead to the higher frequency of certain variants including those involved in disease. Conclusion: We report two Finnish families with hearing impairment due to the CABP2 splice site variant c.637+1G>T.Peer reviewe

Patient Decision Aids for Colorectal Cancer Screening

Decision aids (DAs) prepare patients to make decisions about healthcare options consistent with their preferences. Helping patients choose among available options for colorectal cancer (CRC) screening is important because rates are lower than screening for other cancers. This systematic review describes studies evaluating patient DAs for CRC screening in average-risk adults and their impact on knowledge, screening intentions, and uptake

A High-Density Admixture Scan in 1,670 African Americans with Hypertension

Hypertension (HTN) is a devastating disease with a higher incidence in African Americans than European Americans, inspiring searches for genetic variants that contribute to this difference. We report the results of a large-scale admixture scan for genes contributing HTN risk, in which we screened 1,670 African Americans with HTN and 387 control individuals for regions of the genome with elevated proportion of African or European ancestry. No loci were identified that were significantly associated with HTN. We also searched for evidence of an admixture signal at 40 candidate genes and eight previously reported linkage peaks, but none appears to contribute substantially to the differential HTN risk between African and European Americans. Finally, we observed nominal association at one of the loci detected in the admixture scan of Zhu et al. 2005 (p = 0.016 at 6q24.3 correcting for four hypotheses tested), although we caution that the significance is marginal and the estimated odds ratio of 1.19 per African allele is less than what would be expected from the original report; thus, further work is needed to follow up this locus

A Genomic Pathway Approach to a Complex Disease: Axon Guidance and Parkinson Disease

While major inroads have been made in identifying the genetic causes of rare Mendelian disorders, little progress has been made in the discovery of common gene variations that predispose to complex diseases. The single gene variants that have been shown to associate reproducibly with complex diseases typically have small effect sizes or attributable risks. However, the joint actions of common gene variants within pathways may play a major role in predisposing to complex diseases (the paradigm of complex genetics). The goal of this study was to determine whether polymorphism in a candidate pathway (axon guidance) predisposed to a complex disease (Parkinson disease [PD]). We mined a whole-genome association dataset and identified single nucleotide polymorphisms (SNPs) that were within axon-guidance pathway genes. We then constructed models of axon-guidance pathway SNPs that predicted three outcomes: PD susceptibility (odds ratio = 90.8, p = 4.64 × 10−38), survival free of PD (hazards ratio = 19.0, p = 5.43 × 10−48), and PD age at onset (R2 = 0.68, p = 1.68 × 10−51). By contrast, models constructed from thousands of random selections of genomic SNPs predicted the three PD outcomes poorly. Mining of a second whole-genome association dataset and mining of an expression profiling dataset also supported a role for many axon-guidance pathway genes in PD. These findings could have important implications regarding the pathogenesis of PD. This genomic pathway approach may also offer insights into other complex diseases such as Alzheimer disease, diabetes mellitus, nicotine and alcohol dependence, and several cancers

Analysis of 6,515 exomes reveals a recent origin of most human protein-coding variants

Establishing the age of each mutation segregating in contemporary human populations is important to fully understand our evolutionary history1,2 and will help facilitate the development of new approaches for disease gene discovery3. Large-scale surveys of human genetic variation have reported signatures of recent explosive population growth4-6, notable for an excess of rare genetic variants, qualitatively suggesting that many mutations arose recently. To more quantitatively assess the distribution of mutation ages, we resequenced 15,336 genes in 6,515 individuals of European (n=4,298) and African (n=2,217) American ancestry and inferred the age of 1,146,401 autosomal single nucleotide variants (SNVs). We estimate that ~73% of all protein-coding SNVs and ~86% of SNVs predicted to be deleterious arose in the past 5,000-10,000 years. The average age of deleterious SNVs varied significantly across molecular pathways, and disease genes contained a significantly higher proportion of recently arisen deleterious SNVs compared to other genes. Furthermore, European Americans had an excess of deleterious variants in essential and Mendelian disease genes compared to African Americans, consistent with weaker purifying selection due to the out-of-Africa dispersal. Our results better delimit the historical details of human protein-coding variation, illustrate the profound effect recent human history has had on the burden of deleterious SNVs segregating in contemporary populations, and provides important practical information that can be used to prioritize variants in disease gene discovery

Mitral regurgitation as a phenotypic manifestation of nonphotosensitive trichothiodystrophy due to a splice variant in MPLKIP

Background: Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity. Methods: We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression. Results: Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old. Conclusion: This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype

Positive Selection of a Pre-Expansion CAG Repeat of the Human SCA2 Gene

A region of approximately one megabase of human Chromosome 12 shows extensive linkage disequilibrium in Utah residents with ancestry from northern and western Europe. This strikingly large linkage disequilibrium block was analyzed with statistical and experimental methods to determine whether natural selection could be implicated in shaping the current genome structure. Extended Haplotype Homozygosity and Relative Extended Haplotype Homozygosity analyses on this region mapped a core region of the strongest conserved haplotype to the exon 1 of the Spinocerebellar ataxia type 2 gene (SCA2). Direct DNA sequencing of this region of the SCA2 gene revealed a significant association between a pre-expanded allele [(CAG)(8)CAA(CAG)(4)CAA(CAG)(8)] of CAG repeats within exon 1 and the selected haplotype of the SCA2 gene. A significantly negative Tajima's D value (−2.20, p < 0.01) on this site consistently suggested selection on the CAG repeat. This region was also investigated in the three other populations, none of which showed signs of selection. These results suggest that a recent positive selection of the pre-expansion SCA2 CAG repeat has occurred in Utah residents with European ancestry