Identifying missing pieces in color vision defects: a genome-wide association study in Silk Road populations

Introduction: Color vision defects (CVDs) are conditions characterized by the alteration of normal trichromatic vision. CVDs can arise as the result of alterations in three genes (OPN1LW, OPN1MW, OPN1SW) or as a combination of genetic predisposition and environmental factors. To date, apart from Mendelian CVDs forms, nothing is known about multifactorial CVDs forms. Materials and Methods: Five hundred and twenty individuals from Silk Road isolated communities were genotyped and phenotypically characterized for CVDs using the Farnsworth D-15 color test. The CVDs traits Deutan-Protan (DP) and Tritan (TR) were analysed. Genome Wide Association Study for both traits was performed, and results were corrected with a False Discovery Rate linkage-based approach (FDR-p). Gene expression of final candidates was investigated using a published human eye dataset, and pathway analysis was performed. Results: Concerning DP, three genes: PIWIL4 (FDR-p: 9.01*10-9), MBD2 (FDR-p: 4.97*10-8) and NTN1 (FDR-p: 4.98*10-8), stood out as promising candidates. PIWIL4 is involved in the preservation of Retinal Pigmented Epithelium (RPE) homeostasis while MBD2 and NTN1 are both involved in visual signal transmission. With regards to TR, four genes: VPS54 (FDR-p: 4.09*10-9), IQGAP (FDR-p: 6,52*10-10), NMB (FDR-p: 8.34*10-11), and MC5R (FDR-p: 2.10*10-8), were considered promising candidates. VPS54 is reported to be associated with Retinitis pigmentosa; IQGAP1 is reported to regulate choroidal vascularization in Age-Related Macular Degeneration; NMB is involved in RPE homeostasis regulation; MC5R is reported to regulate lacrimal gland function. Discussion: Overall, these results provide novel insights regarding a complex phenotype (i.e., CVDs) in an underrepresented population such as Silk Road isolated communities

Sarcopenia and bone health: new acquisitions for a firm liaison

Osteosarcopenia (OS) is a newly defined condition represented by the simultaneous presence of osteopenia/osteoporosis and sarcopenia, the main age-related diseases. The simultaneous coexistence of the two phenotypes derives from the close connection of the main target tissues involved in their pathogenesis: bone and muscle. These two actors constitute the bone-muscle unit, which communicates through a biochemical and mechanical crosstalk which involves multiple factors. Altered pattern of molecular pathways leads to an impairment of both the functionality of the tissue itself and the communication with the complementary tissue, composing the OS pathogenesis. Recent advances in the genetics field have provided the opportunity to delve deeper into the complex biological and molecular mechanisms underlying OS. Unfortunately, there are still many gaps in our understanding of these pathways, but it has proven essential to apply strategies such as exercise and nutritional intervention to counteract OS. New therapeutic strategies that simultaneously target bone and muscle tissue are limited, but recently new targets for the development of dual-action drug therapies have been identified. This narrative review aims to provide an overview of the latest scientific evidence associated with OS, a complex disorder that will pave the way for future research aimed at understanding the bone-muscle-associated pathogenetic mechanisms

The Enigmatic Genetic Landscape of Hereditary Hearing Loss: A Multistep Diagnostic Strategy in the Italian Population

Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50–60% of cases, highlighting the relevance of genetic testing in deaf patients. HHL is classified as non-syndromic (NSHL—70% of cases) or syndromic (SHL—30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose GJB2 analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the STRC gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease

Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation

Clinical assessment of skin photosensitivity is subjectively determined by erythema and tanning responses to sunlight recalled by the subject, alternatively known as Fitzpatrick Skin Phototype (SPT). Responses may be unreliable due to recall bias, subjective bias by clinicians and subjects, and lack of cultural sensitivity of the questions. Analysis of red-green-blue (RGB) color spacing of digital images may provide an objective determination of SPT. This paper presents the studies to assess the melanin index (MI), as determined by RGB images obtained by both standard digital camera as well as by videodermoscope, and to correlate the MI with SPT based upon subjects' verbal responses to standardized questions administered by a dermatologist. A sample of subjects representing all SPTs I–VI was selected. Both the digital camera and videodermoscope were calibrated at standard illumination, light source and white balance. Images of constitutive skin of the upper ventral arm were taken of each subject using both instruments. The studies showed that 58 subjects (20 M, 38 F) were enrolled in the study (mean age: 47 years; range: 20–89), stratified to skin phototype I–VI. MI obtained by using both digital camera and videodermoscope increased significantly as the SPT increased (p = 0.004 and p &lt; 0.0001, respectively) and positively correlated with dermatologist-assessed SPT (Spearman correlation, r = 0.48 and r = 0.84, respectively). Digital imaging can quantify melanin content in order to quantitatively approximate skin pigmentation in all skin phototypes including Type VI skin. This methodology holds promise as a simple, non-invasive, rapid and objective approach to reliably determine skin phototype and, with further investigation, may prove to be both practical and useful in the prediction of skin cancer risk.</p

Qualitative assessment of Tongue Drive System by people with high-level spinal cord injury

The Tongue Drive System (TDS) is a minimally invasive, wireless, and wearable assistive technology (AT) that enables people with severe disabilities to control their environments using tongue motion. TDS translates specific tongue gestures into commands by sensing the magnetic field created by a small magnetic tracer applied to the user’s tongue. We have previously quantitatively evaluated the TDS for accessing computers and powered wheelchairs, demonstrating its usability. In this study, we focused on its qualitative evaluation by people with high-level spinal cord injury who each received a magnetic tongue piercing and used the TDS for 6 wk. We used two questionnaires, an after-scenario and a poststudy, designed to evaluate the tongue-piercing experience and the TDS usability compared with that of the sip-and-puff and the users’ current ATs. After study completion, 73% of the participants were positive about keeping the magnetic tongue-barbell in order to use the TDS. All were satisfied with the TDS performance and most said that they were able to do more things using TDS than their current ATs (4.22/5)

Puzzling Out the Genetic Architecture of Endometriosis: Whole-Exome Sequencing and Novel Candidate Gene Identification in a Deeply Clinically Characterised Cohort

Endometriosis (EM) is a common multifactorial gynaecological disorder. Although Genome-Wide Association Studies have largely been employed, the current knowledge of the genetic mechanisms underlying EM is far from complete, and other approaches are needed. To this purpose, whole-exome sequencing (WES) was performed on a deeply characterised cohort of 80 EM patients aimed at the identification of rare and damaging variants within 46 EM-associated genes and novel candidates. WES analysis detected 63 rare, predicted, and damaging heterozygous variants within 24 genes in 63% of the EM patients. In particular, (1) a total of 43% of patients carried variants within 13 recurrent genes (FCRL3, LAMA5, SYNE1, SYNE2, GREB1, MAP3K4, C3, MMP3, MMP9, TYK2, VEGFA, VEZT, RHOJ); (2) a total of 8.8% carried private variants within eight genes (KAZN, IL18, WT1, CYP19A1, IL1A, IL2RB, LILRB2, ZNF366); (3) a total of 24% carried variants within three novel candidates (ABCA13, NEB, CSMD1). Finally, to deepen the polygenic architecture of EM, a comprehensive evaluation of the analysed genes was performed, revealing a higher burden (p < 0.05) of genes harbouring rare and damaging variants in the EM patients than in the controls. These results highlight new insights into EM genetics, allowing for the definition of novel genotype–phenotype correlations, thereby contributing, in a long-term perspective, to the development of personalised care for EM patients

Digital dermoscopy to determine skin melanin index as an objective indicator of skin pigmentation

Clinical assessment of skin photosensitivity is subjectively determined by erythema and tanning responses to sunlight recalled by the subject, alternatively known as Fitzpatrick Skin Phototype (SPT). Responses may be unreliable due to recall bias, subjective bias by clinicians and subjects, and lack of cultural sensitivity of the questions. Analysis of red-green-blue (RGB) color spacing of digital images may provide an objective determination of SPT. This paper presents the studies to assess the melanin index (MI), as determined by RGB images obtained by both standard digital camera as well as by videodermoscope, and to correlate the MI with SPT based upon subjects’ verbal responses to standardized questions administered by a dermatologist.A sample of subjects representing all SPTs I–VI was selected. Both the digital camera and videodermoscope were calibrated at standard illumination, light source and white balance. Images of constitutive skin of the upper ventral arm were taken of each subject using both instruments.The studies showed that 58 subjects (20 M, 38 F) were enrolled in the study (mean age: 47 years; range: 20–89), stratified to skin phototype I–VI. MI obtained by using both digital camera and videodermoscope increased significantly as the SPT increased p = 0.004 and p < 0.0001, respectively) and positively correlated with dermatologist-assessed SPT (Spearman correlation, r = 0.48 and r = 0.84, respectively).Digital imaging can quantify melanin content in order to quantitatively approximate skin pigmentation in all skin phototypes including Type VI skin. This methodology holds promise as a simple, non-invasive, rapid and objective approach to reliably determine skin phototype and, with further investigation, may prove to be both practical and useful in the prediction of skin cancer risk

Genome-Wide Interaction Analyses of Serum Calcium on Ventricular Repolarization Time in 125 393 Participants

Background: Ventricular repolarization time (ECG QT and JT intervals) is associated with malignant arrhythmia. Genome-wide association studies have identified 230 independent loci for QT and JT; however, 50% of their heritability remains unexplained. Previous work supports a causal effect of lower serum calcium concentrations on longer ventricular repolarization time. We hypothesized calcium interactions with QT and JT variant associations could explain a proportion of the missing heritability. Methods and Results: We performed genome-wide calcium interaction analyses for QT and JT intervals. Participants were stratified by their calcium level relative to the study distribution (top or bottom 20%). We performed a 2-stage analysis (genome-wide discovery [N=62 532] and replication [N=59 861] of lead variants) and a single-stage genome-wide meta-analysis (N=122 393, [European ancestry N=117 581, African ancestry N=4812]). We also calculated 2-degrees of freedom joint main and interaction and 1-degree of freedom interaction P values. In 2-stage and single-stage analyses, 50 and 98 independent loci, respectively, were associated with either QT or JT intervals (2-degrees of freedom joint main and interaction P value &lt;5x10(-8)). No lead variant had a significant interaction result after correcting for multiple testing and sensitivity analyses provided similar findings. Two loci in the single-stage meta-analysis were not reported previously (SPPL2B and RFX6). Conclusions: We have found limited support for an interaction effect of serum calcium on QT and JT variant associations despite sample sizes with suitable power to detect relevant effects. Therefore, such effects are unlikely to explain a meaningful proportion of the heritability of QT and JT, and factors including rare variation and other environmental interactions need to be considered

COVID-19 Severity in Multiple Sclerosis: Putting Data Into Context

Background and objectives: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. Methods: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score &gt; 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). Results: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p &lt; 0.001), RR = 2.19 for ICU admission (p &lt; 0.001), and RR = 2.43 for death (p &lt; 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). Discussion: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon