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The remarkable variability of response to vaccines against SARS‐CoV‐2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti‐SARS‐CoV‐2 vaccination with the BNT162b2 vaccine and for whom information about anti‐SARS‐CoV‐2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti‐SARS‐CoV‐2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 × 10−11). In particular, we observed a positive association between the antibody levels and the presence of the HLA‐A*03:01 allele. The same allele was found associated with a 2–2.4‐fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5–1.8‐fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle‐related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus. [ABSTRACT FROM AUTHOR]

Background: Hereditary cardiovascular diseases comprise several different entities. In this study, we focused on cardiomyopathies (i.e., hypertrophic, dilated, arrhythmogenic, and left ventricular non‐compaction), channelopathies (i.e., Brugada syndrome and long QT syndrome), and aortopathies and pulmonary arterial hypertension (i.e., thoracic/abdominal aortic aneurysm and pulmonary arterial hypertension), and genetically characterized 200 Italian patients affected by these diseases. Methods: We employed whole‐exome sequencing (WES), focused on four in silico gene panels, and the MLPA method for hypertrophic and arrhythmogenic right ventricular cardiomyopathy cases. Results: Cardiomyopathies affected 87.5% of analyzed patients, channelopathies 7%, and aortopathies and pulmonary arterial hypertension 5.5%. The molecular diagnosis was confirmed for 21.5% of cases with a higher detection rate in familial forms (34%) than sporadic ones (14%). We highlighted the importance of family segregation to better understand the pathogenic role of the identified variants and their involvement in the clinical phenotype. Negative results could be ascribed to the high genetic and clinical heterogeneity of hereditary cardiovascular diseases; clinical follow‐up and revaluation of WES data will be essential. Conclusion: This study highlights the importance of a multi‐step approach (WES and MLPA) to characterize hereditary cardiovascular diseases, provides crucial information for clinical management and recurrence risk estimation, and lays the foundation for future personalized therapies. [ABSTRACT FROM AUTHOR]

Objectives: Population isolates represent a focus of interest because of their particular genetic history and the possibility of mapping peculiar deleterious variants. Here we investigated the pattern of genetic variation in two North Italian villages: Rotzo (RTZ) and Stoccareddo (STC), in the Asiago plateau. Materials and methods: We genotyped over 800 individuals for more than 600.000 markers. We investigated the isolation level by analyzing runs of homozygosity (ROH) and the level of population structure. Then we estimated the time of admixture and the relationship between ancient genomes and these two villages. Finally, we looked at the effect of genetic drift on deleterious variants. Results: We highlighted a different isolation level between RTZ and STC; despite the average number of ROH being similar between the two villages, RTZ shows a higher level of total homozygosity. We estimated, from different sources, that the time of admixture for the ancestors of these two populations was between 113 and 88 generations ago. We discovered that a deleterious variant in MCUB gene (rs78025076), which is linked to several lipid traits, is entirely absent in RTZ and at 1%frequency in STC. In contrast, the risk allele frequency is 2% in Europe and 2.4% in North‐East Italy. Discussion: These results show the importance of a genetic characterization of geographically isolated populations. Their vast array of past history could highlight specific events in the past and help describe deleterious variants and traits distribution in different regions. [ABSTRACT FROM AUTHOR]

Biallelic mutations in the TTC5 gene have been associated with autosomal recessive intellectual disability (ARID) and subsequently with an ID syndrome including severe speech impairment, cerebral atrophy, and hypotonia as clinical cornerstones. A TTC5 role in IDs has been proposed based on the physical interaction of TTC5 with p300, and possibly reducing p300 co‐activator complex activity, similarly to what was observed in Menke‐Hennekam 1 and 2 patients (MKHK1 and 2) carrying, respectively, mutations in exon 30 and 31 of CREBBP and EP300, which code for the TTC5‐binding region. Recently, TTC5‐related brain malformation has been linked to tubulinopathies due to the function of TTC5 in tubulins' dynamics. We reported seven new patients with novel or recurrent TTC5 variants. The deep characterization of the molecular and phenotypic spectrum confirmed TTC5‐related disorder as a recognizable, very severe neurodevelopmental syndrome. In addition, other relevant clinical aspects, including a severe pre‐ and postnatal growth retardation, cryptorchidism, and epilepsy, have emerged from the reversal phenotype approach and the review of already published TTC5 cases. Microcephaly and facial dysmorphism resulted in being less variable than that documented before. The TTC5 clinical features have been compared with MKHK1 published cases in the hypothesis that clinical overlap in some characteristics of the two conditions was related to the common p300 molecular pathway. [ABSTRACT FROM AUTHOR]

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1−/− mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice. [ABSTRACT FROM AUTHOR]

Background: Periodontitis is a common oral disease caused by host inflammatory response towards bacteria biofilm. The chronic activation of immune response leads to destruction of teeth supporting tissue, bone loss and tooth detachment. Different factors could be involved in the development and severity of the disease; among them the host genetic background should be considered. Objectives: In our study, we analysed haploblocks in a genomic region within major histocompatibility complex (MHC) locus aimed at disclosing a possible correlation with the risk of periodontal disease in 602 adult subjects from North‐East Italy. Results: The CTTAC haploblock (formed by LTA‐rs2857709, LTA‐rs2844484, LTA‐ rs2229094, LTA‐rs2229092 and LTA‐rs1041981 polymorphisms) correlated with protection towards periodontitis condition, after regression analysis including age and smoking status as covariates (P‐value = 0.015). Conclusion: Our results suggest that a haplotype within LTA gene (encoding for lymphotoxin alpha) is involved in the susceptibility towards chronic periodontitis. [ABSTRACT FROM AUTHOR]

Background and Objective: Periodontitis in one of the most prevalent dental diseases. Despite numerous studies have investigated its aetiopathogenetic factors, few works have focused on its genetic predisposition and most of them took into account only candidate genes. Therefore, we conducted a Genome Wide Association Study in an Italian isolated population aimed at uncovering genetic variants that predispose to this disorder. Methods: Diagnosis of chronic periodontitis was made following the criteria of the American Academy of Periodontology. Patients with chronic periodontitis were grouped into different categories: slight, severe, localized and generalized. A control group composed by people without signs of periodontitis or gingivitis was defined. DNA was genotyped using 370k Illumina chips. Linear mixed model regression was used to test the association between each single nucleotide polymorphism (SNP) (independent variable) and the periodontitis status (dependent variable), controlling for confounders sex, age and smoking. The genomic kinship matrix was also used as random effect. Results: Four SNPs on the gene EFCAB4B resulted significantly associated to localized periodontitis (P < 5 × 10−8), with the best hit on the rs242016 SNP (P = 1.5 × 10−8). Conclusion: We have identified a novel significant association between the EFCAB4B gene and localized periodontitis. These results open a new perspective in the understanding of genetic factors contributing to this common disorder. [ABSTRACT FROM AUTHOR]

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The identification of causes underlying intellectual disability (ID) is one of the most demanding challenges for clinical Geneticists and Researchers. Despite molecular diagnostics improvements, the vast majority of patients still remain without genetic diagnosis. Here, we report the results obtained using Whole Exome and Target Sequencing on nine patients affected by isolated ID without pathological copy number variations, which were accurately selected from an initial cohort of 236 patients. Three patterns of inheritance were used to search for: (1) de novo, (2) X-linked, and (3) autosomal recessive variants. In three of the nine proband-parent trios analyzed, we identified and validated two de novo and one X-linked potentially causative mutations located in three ID-related genes. We proposed three genes as ID candidate, carrying one de novo and three X-linked mutations. Overall, this systematic proband-parent trio approach using next generation sequencing could explain a consistent percentage of patients with isolated ID, thus increasing our knowledge on the molecular bases of this disease and opening new perspectives for a better diagnosis, counseling, and treatment. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The article discusses the influence of age, sex and ethnicity on platelet count in five Italian geographic isolates. It states the development of thrombocytopenia derived from the interaction of three factors, genetic factors, which set the basic platelet count, gender-related factors, which result in lower platelet count in men and age-related factors, which are responsible for a progressive decrease in the platelet count over a lifetime.

Deletion of the terminal part of long arm of chromosome 4 is a condition characterized by facial dysmorphisms, cardiac and limb defects, and developmental delay. Deletions usually involve the terminal part of the chromosome and most frequently are interstitial. Here, we report a de novo interstitial deletion resulting in a microdeletion of 6.9 Mb involving 4q31.3-q32.1 segment, detected by SNPs-Array technique in a 4-year-old female showing severe speech delay, mild facial dysmorphisms, and joint laxity. Phenotype-genotype relationships looking at the genes involved in this part of the chromosome were also carried out and data compared with those previously described. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The ability to taste bitter thiourea compounds and related chemicals is a well-known human trait. The majority of individuals perceive these compounds, typified by the bitterness of 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC), as moderately-to-extremely bitter. Approximately 30% of the population is taste blind to these substances. It has been hypothesized that PROP/PTC tasters are more sensitive to other bitter tastes, sweet taste, the pungency of chili peppers, the astringency of alcohol, and the texture of fats. Tasters may also show lower preferences for foods with these taste qualities than nontasters who show the opposite set of responses (i.e., lower taste sensitivities and higher preferences for these sensory qualities). This pathway is illustrated in the following model: Robust associations between PROP status and taste perceptions have been well documented. However, subsequent links to food preferences and diet selection have been more difficult to demonstrate. This is not surprising given the complexity of human ingestive behavior that is influenced by numerous factors including health attitudes, personality traits, and cultural norms. Our laboratory has been using PROP screening to investigate individual differences in the selection of bitter foods, especially bitter tasting vegetables and fruits that may have long-term health implications. This chapter will discuss new and recent findings addressing the following issues: 1) whether PROP-related differences in perception of bitter compounds predict the perception and liking of bitter foods; 2) the role of bitter taste modifiers; and 3) the influence of personal characteristics such as food attitudes and cultural background on PROP-related food preferences. [ABSTRACT FROM AUTHOR]

The article focuses on a study which determined whether variation in the bitter-taste receptor gene, TAS2R38, is associated with adiposity in a genetically isolated population in Carlantino in southern Italy. The study participants were composed of 540 healthy individuals who were 15 to 89 years of age at the time of the study. Variables measured included body mass index (BMI) and waist circumference (WC) in females. A detailed discussion on the study findings is presented.

Phytosterolaemia (sitosterolaemia) is a recessively inherited metabolic condition in which the absorption of both cholesterol and plant-derived cholesterol-like molecules at the gut is unselective and unrestricted. In haematology, Mediterranean stomatocytosis or Mediterranean macrothrombocytopenia is a poorly understood haematological condition that combines stomatocytic haemolysis with the presence of very large platelets. Five pedigrees showing this haematology were identified. Gas chromatography mass spectrometry (GC-MS) showed that all of the patients with this highly specific haematology had grossly elevated levels of phytosterols in the blood, diagnostic of phytosterolaemia. All showed mutations in the ABCG5 and ABCG8 previously linked to phytosterolaemia. Three pedigrees showed five new mutations, while two pedigrees showed the common W361X mutation in ABCG8. We draw the following four conclusions: (i) that Mediterranean stomatocytosis/macrothrombocytopenia is caused by an excess of phytosterols in the blood; (ii) that phytosterolaemia, which does not respond to standard statin treatment, can be diagnosed via the distinctive haematology described here, even when the cholesterol is normal; (iii) that phytosterolaemia should be considered in the differential diagnosis of all patients with large platelets; and (iv) that the platelet size should be noted in patients with hypercholesterolaemia. [ABSTRACT FROM AUTHOR]

Summary. Juvenile haemochromatosis or haemochromatosis type 2 is a rare autosomal recessive disorder which causes iron overload at a young age, affects both sexes equally and is characterized by a prevalence of hypogonadism and cardiopathy. Patients with haemochromatosis type 2 have been reported in different ethnic groups. Linkage to chromosome 1q has been established recently, but the gene remains unknown. We report the analysis of the phenotype of 29 patients from 20 families of different ethnic origin with a juvenile 1q-associated disease. We also compared the clinical expression of 26 juvenile haemochromatosis patients with that of 93 C282Y homozygous males and of 11 subjects with haemochromatosis type 3. Patients with haemochromatosis type 2 were statistically younger at presentation and had a more severe iron burden than C282Y homozygotes and haemochromatosis type 3 patients. They were more frequently affected by cardiopathy, hypogonadism and reduced glucose tolerance. In contrast cirrhosis was not statistically different among the three groups. These data suggest that the rapid iron accumulation in haemochromatosis type 2 causes preferential tissue damage. Our results clarify the natural history of the disease and are compatible with the hypothesis that the HFE2 gene has greater influence on iron absorption than other haemochromatosis-associated genes. [ABSTRACT FROM AUTHOR]

Regular blood transfusions from infancy until adulthood in β-thalassaemia major patients have substituted severe bone deformities with less marked skeletal lesions as osteoporosis. Osteoporosis is characterized by low bone mass and disruption of bone architecture, resulting in reduced bone strength and increased risk of fractures. Genetic factors have an important role in determining bone mineral density (BMD). We have investigated the possible association between BMD and two polymorphisms in 135 β-thalassaemic patients: (i) a substitution G→Τ in a regulatory region of the COLIA1 gene encoding for the major protein of bone (type 1 collagen), and (ii) a one-base deletion in intron 4 (713–8del C) of transforming growth factor beta 1 (TGF-β1) gene. We have found a remarkable incidence (90%) of osteopenia and osteoporosis among regularly transfused patients. Bone mass was lower in men than in women (P = 0·0023), with a more prevalent osteopenia/osteoporosis of the spine in men than in women (P = 0·001). The sample was stratified on the basis of BMD expressed as Z-score, i.e. normal, osteopenic and osteoporotic patients, and genotype frequencies of each group were evaluated. TGF-β1 polymorphism failed to demonstrate a statistical difference in BMD groups. However, subjects with heterozygous or homozygous polymorphism of the COLIA1 gene showed a lower BMD than subjects without the sequence variation (P = 0·012). The differences among genotypes were still present when the BMD was analysed as adjusted Z-score and when men and women were analysed separately (P = 0·022 and 0·004 respectively), with men more severely affected. Analysis of COLIA1 polymorphism could help to identify those thalassaemic patients at risk of osteoporosis and fractures. [ABSTRACT FROM AUTHOR]

Background: Warsaw Breakage Syndrome (WABS) is an ultra rare cohesinopathy caused by biallelic mutation of DDX11 gene. It is clinically characterized by pre and postnatal growth delay, microcephaly, hearing loss with cochlear hypoplasia, skin color abnormalities, and dysmorphisms. Methods: Mutational screening and functional analyses (protein expression and 3D‐modeling) were performed in order to investigate the presence and pathogenicity of DDX11 variant identified in our patients. Results: We report the clinical history of two sisters affected by WABS with a pathological mytomicin C test carrying compound heterozygous mutations (c.2507T > C / c.907_920del) of the DDX11 gene. The pathogenicity of this variant was confirmed in the light of a bioinformatic study and protein three‐dimensional modeling, as well as expression analysis. Conclusion: These findings further extend the clinical and molecular knowledge about the WABS showing a possible mild phenotype without major malformations or intellectual disability. [ABSTRACT FROM AUTHOR]

Esophageal atresia/tracheoesophageal fistula (EA/TEF) is a life-threatening birth defect that often occurs with other major birth defects (EA/TEF+). Despite advances in genetic testing, a molecular diagnosis can only be made in a minority of EA/TEF+ cases. Here, we analyzed clinical exome sequencing data and data from the DECIPHER database to determine the efficacy of exome sequencing in cases of EA/TEF+ and to identify phenotypic expansions involving EA/TEF. Among 67 individuals with EA/TEF+ referred for clinical exome sequencing, a definitive or probable diagnosis was made in 11 cases for an efficacy rate of 16% (11/67). This efficacy rate is significantly lower than that reported for other major birth defects, suggesting that polygenic, multifactorial, epigenetic, and/or environmental factors may play a particularly important role in EA/TEF pathogenesis. Our cohort included individuals with pathogenic or likely pathogenic variants that affect TCF4 and its downstream target NRXN1, and FANCA, FANCB, and FANCC, which are associated with Fanconi anemia. These cases, previously published case reports, and comparisons to other EA/TEF genes made using a machine learning algorithm, provide evidence in support of a potential pathogenic role for these genes in the development of EA/TEF., (© 2022 Wiley Periodicals LLC.)

Stickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176&#95;1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis., (© 2013 Wiley Periodicals, Inc.)

Cohen syndrome, caused by mutations in the COH1 gene, is an autosomal recessive disorder consisting of mental retardation, microcephaly, growth delay, severe myopia, progressive chorioretinal dystrophy, facial anomalies, slender limbs with narrow hands and feet, tapered fingers, short stature, kyphosis and/or scoliosis, pectus carinatum, joint hypermobility, pes calcaneovalgus, and, variably, truncal obesity. Here, we describe the clinical and molecular findings in 14 patients from an isolated Greek island population. The clinical phenotype was fairly homogeneous, although microcephaly was not constant, and some patients had severe visual disability. All patients were homozygous for a novel intragenic COH1 deletion spanning exon 6 to exon 16, suggesting a founder effect. The discovery of this mutation has made carrier detection and prenatal diagnosis possible in this population., ((c) 2008 Wiley-Liss, Inc.)