Supernumerary teeth (ST) are odontostomatologic anomaly characterized by as the existence excessive number of teeth in relation to the normal dental formula. This condition is commonly seen with several congenital genetic disorders such as Gardner's syndrome, cleidocranial dysostosis and cleft lip and palate. Less common syndromes that are associated with ST are; Fabry Disease, Ellis-van Creveld syndrome, Nance-Horan syndrome, Rubinstein-Taybi Syndrome and Trico-Rhino-Phalangeal syndrome. ST can be an important component of a distinctive disorder and an important clue for early diagnosis. Certainly early detecting the abnormalities gives us to make correct management of the patient and also it is important for making well-informed decisions about long-term medical care and treatment. In this review, the genetic syndromes that are related with ST were discussed.

Acromegaly is caused by a somatotropinoma in the vast majority of the cases. These are monoclonal tumors that can occur sporadically or rarely in a familial setting. In the last few years, novel familial syndromes have been described and recent studies explored the landscape of somatic mutations in sporadic somatotropinomas. This short review concentrates on the current knowledge of the genetic basis of both familial and sporadic acromegaly.

The phenotypic consequence of a given mutation can be influenced by the genetic background. For example, conditional gene essentiality occurs when the loss of function of a gene causes lethality in one genetic background but not another. Between two individual Saccharomyces cerevisiae strains, S288c and Σ1278b, ∼1% of yeast genes were previously identified as "conditional essential." Here, in addition to confirming that some conditional essential genes are modified by a nonchromosomal element, we show that most cases involve a complex set of genomic modifiers. From tetrad analysis of S288C/Σ1278b hybrid strains and whole-genome sequencing of viable hybrid spore progeny, we identified complex sets of multiple genomic regions underlying conditional essentiality. For a smaller subset of genes, including CYS3 and CYS4, each of which encodes components of the cysteine biosynthesis pathway, we observed a segregation pattern consistent with a single modifier associated with conditional essentiality. In natural yeast isolates, we found that the CYS3/CYS4 conditional essentiality can be caused by variation in two independent modifiers, MET1 and OPT1, each with roles associated with cellular cysteine physiology. Interestingly, the OPT1 allelic variation appears to have arisen independently from separate lineages, with rare allele frequencies below 0.5%. Thus, while conditional gene essentiality is usually driven by genetic interactions associated with complex modifier architectures, our analysis also highlights the role of functionally related, genetically independent, and rare variants.

Genetic interactions between mutations and standing polymorphisms can cause mutations to show distinct phenotypic effects in different individuals. To characterize the genetic architecture of these so-called background effects, we genotype 1411 wild-type and mutant yeast cross progeny and measure their growth in 10 environments. Using these data, we map 1086 interactions between segregating loci and 7 different gene knockouts. Each knockout exhibits between 73 and 543 interactions, with 89% of all interactions involving higher-order epistasis between a knockout and multiple loci. Identified loci interact with as few as one knockout and as many as all seven knockouts. In mutants, loci interacting with fewer and more knockouts tend to show enhanced and reduced phenotypic effects, respectively. Cross-environment analysis reveals that most interactions between the knockouts and segregating loci also involve the environment. These results illustrate the complicated interactions between mutations, standing polymorphisms, and the environment that cause background effects.

Paroxysmal epileptiform abnormalities on electroencephalography (EEG) are the hallmark of epilepsies, but it is uncertain to what extent epilepsy and background EEG oscillations share neurobiological underpinnings. Here, we aimed to assess the genetic correlation between epilepsy and background EEG oscillations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by degeneration of the right ventricle and ventricular tachycardia originating from the right ventricle. Additionally, the disease is an inherited cardiomyopathy that mainly follows the autosomal dominant pattern. More than 10 genes have been reported as causative genes for ARVC, and more than half of ARVC patients carry mutations in desmosome related genes. The desmosome is one of the structures involved in cell adhesion and its disruption leads to various diseases, including a skin disease called pemphigus. Among desmosome genes, mutations in PKP2 are most frequently identified in ARVC patients. Although the genotype-phenotype correlations remain to be fully studied, many studies have reported clinical manifestations of, prognosis for, and appropriate therapies for ARVC from the perspective of gene mutations. A collective review of these reports would enhance the understanding of ARVC pathogenesis and clinical manifestation. This review discusses the clinical issues of ARVC from the genetic background.

Genome-wide association studies (GWASs) have identified numerous loci that influence risk for psychiatric diseases. Genetically engineered mice are often used to characterize genes implicated by GWASs. These studies are based on the assumption that observed genotype-phenotype relationships will generalize to humans, implying that the results would at least generalize to other inbred mouse strains. Given current concerns about reproducibility, we sought to directly test this assumption. We produced F1 crosses between male C57BL/6J mice heterozygous for null alleles of Cacna1c and Tcf7l2 and wild-type females from 30 inbred laboratory strains. We found extremely strong interactions with genetic background that sometimes supported diametrically opposing conclusions. These results do not negate the invaluable contributions of mouse genetics to biomedical science, but they do show that genotype-phenotype relationships cannot be reliably inferred by studying a single genetic background, and thus constitute a major challenge to the status quo. VIDEO ABSTRACT.

Empathy, as originally defined, refers to an emotional experience that is shared among individuals. When discomfort or alarm is detected in another, a variety of behavioral responses can follow, including greater levels of nurturing, consolation or increased vigilance towards a threat. Moreover, changes in systemic physiology often accompany the recognition of distressed states in others. Employing a mouse model of cue-conditioned fear, we asked whether exposure to conspecific distress influences how a mouse subsequently responds to environmental cues that predict this distress. We found that mice are responsive to environmental cues that predict social distress, that their heart rate changes when distress vocalizations are emitted from conspecifics, and that genetic background substantially influences the magnitude of these responses. Specifically, during a series of pre-exposure sessions, repeated experiences of object mice that were exposed to a tone-shock (CS-UCS) contingency resulted in heart rate deceleration in subjects from the gregarious C57BL/6J (B6) strain, but not in subjects from the less social BALB/cJ (BALB) strain. Following the pre-exposure sessions, subjects were individually presented with the CS-only for 5 consecutive trials followed by 5 consecutive pairings of the CS with the UCS. Pre-exposure to object distress increased the freezing responses of B6 mice, but not BALB mice, on both the CS-only and the CS-UCS trials. These physiological and behavioral responses of B6 mice to social distress parallel features of human empathy. Our paradigm thus has construct and face validity with contemporary views of empathy, and provides unequivocal evidence for a genetic contribution to the expression of empathic behavior.

The influence of genetic background on the ability to generate induced pluripotent stem cells (iPSCs) has the potential to impact future applications, but has yet to be examined in detail. The purpose of this study was to determine if genetic background affects the efficiency of generating iPSCs during early reprograming as well as the pluripotent stability of the iPSCs during later stages of reprograming.

Hematotoxicity is a life-threatening side effect of many chemotherapy regimens. Although clinical factors influence patient responses, genetic factors may also play an important role. We sought to identify genomic loci that influence chemotherapy-induced hematotoxicity by dosing Diversity Outbred mice with one of three chemotherapy drugs; doxorubicin, cyclophosphamide or docetaxel. We observed that each drug had a distinct effect on both the changes in blood cell subpopulations and the underlying genetic architecture of hematotoxicity. For doxorubicin, we mapped the change in cell counts before and after dosing and found that alleles of ATP-binding cassette B1B (Abcb1b) on chromosome 5 influence all cell populations. For cyclophosphamide and docetaxel, we found that each cell population was influenced by distinct loci, none of which overlapped between drugs. These results suggest that susceptibility to chemotherapy-induced hematotoxicity is influenced by different genes for different chemotherapy drugs.

Thrombosis is the fatal and disabling consequence of cardiovascular diseases, the leading cause of mortality and morbidity in Western countries. Two inbred mouse strains, C57BL/6J and A/J, have marked differences in susceptibility to obesity, atherosclerosis, and vessel remodeling. However, it is unclear how these diverse genetic backgrounds influence pathways known to regulate thrombosis and hemostasis. The objective of this study was to evaluate thrombosis and hemostasis in these two inbred strains and determine the phenotypic response of A/J chromosomes in the C57BL/6J background.

Freezing behavior is used as a measure of a rodent's ability to learn during fear conditioning. However, it is possible that the expression of other behaviors may compete with freezing, particularly in rodent populations that have not been thoroughly studied in this context. Rearing and grooming are complex behaviors that are frequently exhibited by mice during fear conditioning. Both behaviors have been shown to be stress-sensitive, and the expression of these behaviors is dependent upon strain background. To better understand how genetic background impacts behavioral responses during fear conditioning, we examined freezing, rearing, and grooming frequencies prior to fear conditioning training and across different stages of fear conditioning testing in male mice from eight inbred mouse strains (C57BL/6J, DBA/2J, FVB/NJ, SWR/J, BTBR T + ltpr3Tf/J, SM/J, LP/J, 129S1/SvlmJ) that exhibited diverse freezing responses. We found that genetic background determined rearing and grooming expression throughout fear conditioning, and their patterns of expression across stages of fear conditioning were strain dependent. Using publicly available SNP data, we found that polymorphisms in Dab1, a gene that is implicated in both grooming and learning phenotypes, separated the strains with high contextual grooming from the others using a hierarchical clustering analysis. This suggested a potential genetic mechanism for the observed behavioral differences. These findings demonstrate that genetic background determines behavioral responses during fear conditioning and suggest that shared genetic substrates underlie fear conditioning behaviors.

While cochlear implantation (CI) technology has greatly improved over the past 40 years, one aspect of CI that continues to pose difficulties is the variability of outcomes due to numerous factors involved in postimplantation performance. The electric acoustic stimulation (EAS) system has expanded indications for CI to include patients with residual hearing, and is currently becoming a standard therapy for these patients. Genetic disorders are known to be the most common cause of congenital/early-onset sensorineural hearing loss, and are also involved in a considerable proportion of cases of late-onset hearing loss. There has been a great deal of progress in the identification of deafness genes over the last two decades. Currently, more than 100 genes have been reported to be associated with non-syndromic hearing loss. Patients possessing a variety of deafness gene mutations have achieved satisfactory auditory performance after CI/EAS, suggesting that identification of the genetic background facilitates prediction of post-CI/EAS performance. When the intra-cochlear etiology is associated with a specific genetic background, there is a potential for good CI performance. Thus, it is essential to determine which region of the cochlea is affected by identifying the responsible genes. This review summarizes the genetic background of the patients receiving CI/EAS, and introduces detailed clinical data and CI/EAS outcomes in representative examples. Anat Rec, 303:563-593, 2020. © 2020 The Authors. The Anatomical Record published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists.

Peroxisome proliferator-activated receptors (PPAR gamma-2) and beta-3-adrenergic receptors (ADRB3) are involved in the risk of hypertension. But their exact role in blood pressure modulation in patients with connective tissue diseases (CTD) is still not well defined. In this study, 104 patients with CTD and 103 gender- and age-matched controls were genotyped for Pro12Ala and C1431T polymorphisms of the PPAR gamma-2 gene and Trp64Arg polymorphism of the ADRB gene. Anthropometric and biochemical measurements were evaluated, followed by genotyping using TaqMan® SNP genotyping assays and polymerase chain reaction-restriction fragment length polymorphism. The prevalence of analyzed genotypes and alleles was comparable between patients with CTD and the control group, as well as hypertensive and normotensive subjects. Patients with CTD have lower body fat and higher body water amount, serum glucose, and triglyceride (TG) levels. Hypertensive subjects are older and have higher body mass, BMI, waist circumference (WC), body water content, glucose, and TG concentration. The multivariate analysis revealed that hypertensive subjects with Ala12/X or Trp64Trp have higher body mass and WC when compared to normotensive subjects. Trp64Trp polymorphism was also characterized by a higher TG level, while T1431/X subjects had higher WC. The presence of CTD, visceral fat distribution, and increased age are the predictors of hypertension development. Hypertensive patients with CTD and Trp64Trp polymorphism have an increased risk of visceral obesity development and metabolic complications, which in turn affects the value of blood pressure. In addition, either Ala12/X or T1431/X predicts the visceral body fat distribution in hypertensive subjects.

Genetic service for couples plays an increasingly important role in diagnosis and risk management. This study investigated the status of consanguinity and the medical genetic history (effectiveness and coverage of medical genetic services) in couples residing in a city in southern Iran. We questioned couples who were referred to Behbahan Marital Counseling Center, Behbahan, Iran, during the period from January to November 2014, to obtain information on consanguinity, disease history, and previous referral to a medical genetics center. For the collected data was obtained descriptive statistics with STATA 11.0 software. A total of 500 couples were questioned. Mean age was 24.8 ± 5.2 years. Almost one quarter (23.4%) of the couples were consanguineous. Consanguinity was almost twice as common in rural areas as in urban areas (33.9 vs. 19.2%, p = 0.001). Only a few couples (~3.0%) had ever been referred for genetic counseling. The main reason for previous genetic counseling was consanguinity (85.7%). The majority of the participants (96.3%) had never been tested for any genetic conditions. Our findings suggest that only a small proportion of couples in Khuzestan Province, Iran (Behbahan City) were receiving adequate genetics care. This may reflect the limited accessibility of such services, and inadequate awareness and education among the care providers.

Genetic testing for congenital or early-onset hearing loss patients has become a common diagnostic option in many countries. On the other hand, there are few late-onset hearing loss patients receiving genetic testing, as late-onset hearing loss is believed to be a complex disorder and the diagnostic rate for genetic testing in late-onset patients is lower than that for the congenital cases. To date, the etiology of late-onset hearing loss is largely unknown. In the present study, we recruited 48 unrelated Japanese patients with late-onset bilateral sensorineural hearing loss, and performed genetic analysis of 63 known deafness gene using massively parallel DNA sequencing. As a result, we identified 25 possibly causative variants in 29 patients (60.4%). The present results clearly indicated that various genes are involved in late-onset hearing loss and a significant portion of cases of late-onset hearing loss is due to genetic causes. In addition, we identified two interesting cases for whom we could expand the phenotypic description. One case with a novel MYO7A variant showed a milder phenotype with progressive hearing loss and late-onset retinitis pigmentosa. The other case presented with Stickler syndrome with a mild phenotype caused by a homozygous frameshift COL9A3 variant. In conclusion, comprehensive genetic testing for late-onset hearing loss patients is necessary to obtain accurate diagnosis and to provide more appropriate treatment for these patients.

Much remains unknown about the progression and heterogeneity of mutational processes in different cancers and their diagnostic and clinical potential. A growing body of evidence supports mutation rate dependence on the local DNA sequence context for various types of mutations. We propose several tools for the analysis of cancer context-dependent mutations, which are implemented in an online computational framework MutaGene. The framework explores DNA context-dependent mutational patterns and underlying somatic cancer mutagenesis, analyzes mutational profiles of cancer samples, identifies the combinations of underlying mutagenic processes including those related to infidelity of DNA replication and repair machinery, and various other endogenous and exogenous mutagenic factors. As a result, the combination of mutagenic processes can be identified in any query sample with subsequent comparison to mutational profiles derived from malignant and benign samples. In addition, mutagen or cancer-specific mutational background models are applied to calculate expected DNA and protein site mutability to decouple relative contributions of mutagenesis and selection in carcinogenesis, thus elucidating the site-specific driving events in cancer. MutaGene is freely available at https://www.ncbi.nlm.nih.gov/projects/mutagene/.

Recently, nephronophthisis (NPH) has been considered a monogenic cause of end-stage renal disease (ESRD) in adults. However, adult-onset NPH is difficult to accurately diagnose and has not been reported in a cohort study. In this study, we assessed the genetic background and clinicopathologic features of adult NPH.

Genetic modifiers can be detected in mice by looking for strain background differences in inheritance or phenotype of a mutation. They can be mapped by analyses of appropriate linkage crosses and congenic lines, and modifier genes of large effect can be identified by positional-candidate gene testing. Inbred strains of mice vary widely in onset and severity of age-related hearing loss (AHL), an important consideration when assessing hearing in mutant mice. At least 8 mapped loci and a mitochondrial variant (mt-Tr) are known to contribute to AHL in mouse strains; one locus (ahl) has been identified as a variant of the cadherin 23 gene (Cdh23(753A/G)). This variant also was shown to modify hearing loss associated with the Atp2b2(dfw-2J) and Mass1(frings) mutations. The hearing modifier (Moth1) of tubby (Tub(tub)) mutant mice was shown to be a strain variant of the Mtap1a gene. Human hearing modifiers include DFNM1, which suppresses recessive deafness DFNB26, and a nuclear gene that modulates the severity of hearing loss associated with a mitochondrial mutation. Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice. Because modifier genes and digenic inheritance are not always distinguishable, we also include in this review several examples of digenic inheritance of hearing loss that have been reported in both mice and humans.

Multiple endocrine neoplasia type 1 (MEN1), an autosomal dominant disorder caused by MEN1 germline mutations, is characterised by parathyroid, pancreatic and pituitary tumours. MEN1 mutations also cause familial isolated primary hyperparathyroidism (FIHP), a milder condition causing hyperparathyroidism only. Identical mutations can cause either MEN1 or FIHP in different families, thereby implicating a role for genetic modifiers in altering phenotypic expression of tumours. We therefore investigated the effects of genetic background and potential for genetic modifiers on tumour development in adult Men1+/- mice, which develop tumours of the parathyroids, pancreatic islets, anterior pituitary, adrenal cortex and gonads, that had been backcrossed to generate C57BL/6 and 129S6/SvEv congenic strains. A total of 275 Men1+/- mice, aged 5-26 months were macroscopically studied, and this revealed that genetic background significantly influenced the development of pituitary, adrenal and ovarian tumours, which occurred in mice over 12 months of age and more frequently in C57BL/6 females, 129S6/SvEv males and 129S6/SvEv females, respectively. Moreover, pituitary and adrenal tumours developed earlier, in C57BL/6 males and 129S6/SvEv females, respectively, and pancreatic and testicular tumours developed earlier in 129S6/SvEv males. Furthermore, glucagon-positive staining pancreatic tumours occurred more frequently in 129S6/SvEv Men1+/- mice. Whole genome sequence analysis of 129S6/SvEv and C57BL/6 Men1+/- mice revealed >54,000 different variants in >300 genes. These included, Coq7, Dmpk, Ccne2, Kras, Wnt2b, Il3ra and Tnfrsf10a, and qRT-PCR analysis revealed that Kras was significantly higher in pituitaries of male 129S6/SvEv mice. Thus, our results demonstrate that Kras and other genes could represent possible genetic modifiers of Men1.