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To date, approximately 500 monogenic inherited kidney diseases have been reported, with more than 50 genes associated with the pathogenesis of monogenic isolated or syndromic nephrotic syndrome. Most of these genes are expressed in podocytes of the glomerulus. Neurological symptoms are common extrarenal manifestations of syndromic nephrotic syndrome, and various studies have found connections between podocytes and neurons in terms of morphology and function. This review summarizes the genetic and clinical characteristics of monogenic inherited diseases with concomitant glomerular and central nervous system lesions, aiming to enhance clinicians' understanding of such diseases, recognize the importance of genetic diagnostic techniques for comorbidity screening, and reduce the rates of missed diagnosis and misdiagnosis.

An ESHG-ESHRE survey on the current practice of expanded carrier screening in medically assisted reproduction.

STUDY QUESTION: What is the current practice and views on (expanded) carrier screening ((E)CS) among healthcare professionals in medically assisted reproductive (MAR) practices in Europe? SUMMARY ANSWER: The findings show a limited support for ECS with less than half of the respondents affiliated to centres offering ECS, and substantial variation in practice between centres in Europe. WHAT IS KNOWN ALREADY: The availability of next-generation sequencing, which enables testing for large groups of genes simultaneously, has facilitated the introduction and expansion of ECS strategies, currently offered particularly in the private sector in the context of assisted reproduction. STUDY DESIGN, SIZE, DURATION: A cross-sectional survey evaluating practice and current views among professionals working in MAR practice in different European countries was designed using the online SurveyMonkey tool. The web-based questionnaire included questions on general information regarding the current practice of (E)CS in MAR and questions on what is offered, to whom the test is offered, and how it is offered. It consisted mostly of multiple-choice questions with comment boxes, but also included open questions on the respondents' attitudes/concerns relevant to (E)CS practice, and room to upload requested files (e.g. guidelines and gene panels). In total, 338 responses were collected from 8 February 2022 to 11 April 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: The online survey was launched with an invitation email from the ESHRE central office (n = 4889 emails delivered) and the European Society of Human Genetics (ESHG) central office (n = 1790 emails delivered) sent to the ESHRE and ESHG members, and by social media posts. The survey was addressed to European MAR centres or gamete banks and to centres located in non-European countries participating in the European IVF-monitoring Consortium. Two reminder emails were sent. After exclusion of 39 incomplete responses received (e.g. only background information), 299 respondents from 40 different countries were included for analyses. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, 42.5% (127/299) of respondents were affiliated to centres offering ECS. The perceived responsibility to enable prospective parents to make informed reproductive decisions and preventing suffering/burden for parents were the main reasons to offer ECS. A single ECS panel is offered by nearly 45% (39/87 received answers) of the centres offering ECS, 25.3% (22/87) of those centres offer a selection of ECS panels, and 29.9% (26/87) offer whole exome sequencing and a large in silico panel. Different ranges of panel sizes and conditions were included in the ECS panel(s) offered. Most of the respondents (81.8%; 72/88 received answers) indicated that the panels they offer are universal and target the entire population. Pathogenic variants (89.7%; 70/78 received answers), and to a lesser extent, likely pathogenic variants (64.1%%; 50/78 received answers), were included in the ECS report for individuals and couples undergoing MAR with their own gametes. According to 87.9% (80/91 received answers) of the respondents, patients have to pay to undergo an ECS test. Most respondents (76.2%; 61/80 received answers) reported that counselling is provided before and after the ECS test. Preimplantation genetic testing, the use of donor gametes, and prenatal diagnostic testing were the three main reproductive options discussed with identified carrier couples. The main reason, according to the respondents, for not offering ECS in their centre, was the lack of professional recommendations supporting ECS (52.5%; 73/139 received answers) and the high cost for couples or reimbursement not being available (49.6%; 69/139). The challenges and moral dilemmas encountered by the respondents revolved mainly around the content of the offer, including the variants classification and the heterogeneity of the panels, the counselling, and the cost of the test. LIMITATIONS, REASONS FOR CAUTION: Although the total number of respondents was acceptable, the completion rate of the survey was suboptimal. In addition, the heterogeneity of answers to open-ended questions and the ambiguity of some of the answers, along with incomplete responses, posed a challenge in interpreting survey results. It is also plausible that some questions were not easily understood by the respondents. For this reason, response and non-response bias are acknowledged as further limitations of the survey. WIDER IMPLICATIONS OF THE FINDINGS: The results of this survey could aid in identifying potential challenges or areas for improvement in the current practice of ECS in the MAR field and contribute to the discussion on how to address them. The results underline the need to stimulate a more knowledge-based debate on the complexity and the pros and cons of a possible implementation of ECS in MAR. STUDY FUNDING/COMPETING INTEREST(S): All costs relating to the development process were covered from European Society of Human Reproduction and Embryology and European Society of Human Genetics funds. There was no external funding of the development process or manuscript production. A.C. is full-time employee of Juno Genetics. L.H. declared receiving a research grant during the past 36 months from the Netherlands Organisation for Health Research and Development. She has also participated in a Health Council report of the Netherlands on preconception carrier screening and collaborated with the VSOP Dutch Genetic Alliance (patient umbrella organization on rare and genetic disorders). L.H. and C.v.E. are affiliated with Amsterdam University Medical Centre, a hospital that offers ECS in a non-commercial setting. R.V. received honoraria for presentations from Merck Academy and is unpaid board member of the executive committee of the Spanish Fertility Society. The other authors had nothing to disclose. TRIAL REGISTRATION NUMBER: N/A.

Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense.

Oxidative stress, characterized by an imbalance between the production of reactive oxygen species (ROS) and the cellular anti-oxidant defense mechanisms, plays a critical role in the pathogenesis of various human diseases. Redox metabolism, comprising a network of enzymes and genes, serves as a crucial regulator of ROS levels and maintains cellular homeostasis. This review provides an overview of the most important human genes encoding for proteins involved in ROS generation, ROS detoxification, and production of reduced nicotinamide adenine dinucleotide phosphate (NADPH), and the genetic disorders that lead to dysregulation of these vital processes. Insights gained from studies on inherited monogenic metabolic diseases provide valuable basic understanding of redox metabolism and signaling, and they also help to unravel the underlying pathomechanisms that contribute to prevalent chronic disorders like cardiovascular disease, neurodegeneration, and cancer.

Special Issue: "Canine Genetics 2".

Wolves were the first animal species to become domesticated by humans, approximately 30,000-50,000 years ago. Human-directed dog breeding over thousands of generations has generated more than 350 recognized breeds displaying surprisingly different phenotypes with respect to morphology, behavior and disease predispositions. The domestication of wolves and the subsequent breeding of dogs can be viewed as one of humankind's oldest and largest genetic experiments and provides us with unique opportunities for research. Dogs have not only become human's best friend but were also described as geneticists' best friend in a past issue of Science. In recognition of the importance of canine genetics, this Special Issue, entitled "Canine Genetics 2", was compiled. It represents a sequel to the former Special Issue "Canine Genetics", which was published in 2019. During the last 15 years, the canine community has heavily relied on a reference genome derived from the female Boxer Tasha. "Canine Genetics 2" includes an article describing a greatly improved version of this important community resource. This Special Issue further contains several reports related to monogenic or complex inherited diseases in dogs. Finally, important aspects of wild canid research, genetic diversity in different populations and canine morphology were investigated.

Severe congenital X-linked myopathy with excessive autophagy secondary to an apparently synonymous but pathogenic novel variant.

X-linked myopathy with excessive autophagy is a rare inherited disease characterized by aberrant accumulation of autophagic vacuoles in skeletal muscle. Affected males usually show a slow progression and the heart is characteristically spared. We present four male patients from the same family with an extremely aggressive form of this disease, requiring permanent mechanical ventilation from birth. Ambulation was never achieved. Three died, one in the first hour of life, one at 7 years and one at 17 years, the last death being a consequence of heart failure. Muscle biopsy showed pathognomonic features of the disease in the 4 affected males. Genetic study found a novel synonymous variant in VMA21, c.294C>T (Gly98=). Genotyping was consistent with co-segregation with the phenotype in an X-linked recessive manner. An alteration of the normal splice pattern was confirmed by transcriptome analysis, proving that the apparently synonymous variant was the cause of this extremely severe phenotype.

Does genetic testing offer utility as a supplement to traditional family health history intake for inherited disease risk?

CONTENT: This study examines the potential utility of genetic testing as a supplement to family health history to screen for increased risk of inherited disease. Medical conditions are often misreported or misunderstood, especially those related to different forms of cardiac disease (arrhythmias vs. structural heart disease vs. coronary artery disease), female organ cancers (uterine vs. ovarian vs. cervical), and type of cancer (differentiating primary cancer from metastases to other organs). While these nuances appear subtle, they can dramatically alter medical management. For example, different types of cardiac failure (structural, arrhythmia, and coronary artery disease) have inherited forms that are managed with vastly different approaches. METHODS: Using a dataset of over 6,200 individuals who underwent genetic screening, we compared the ability of genetic testing and traditional family health history to identify increased risk of inherited disease. A further, in-depth qualitative study of individuals for whom risk identified through each method was discordant, explored whether this discordance could be addressed through changes in family health history intake. FINDINGS: Of 90 individuals for whom genetic testing indicated significant increased risk for inherited disease, two-thirds (66%) had no corroborating family health history. Specifically, we identify cardiomyopathy, arrhythmia, and malignant hyperthermia as conditions for which discordance between genetic testing and traditional family health history was greatest, and familial hypercholesterolaemia, Lynch syndrome, and hereditary breast and ovarian cancer as conditions for which greater concordance existed. CONCLUSION: We conclude that genetic testing offers utility as a supplement to traditional family health history intake over certain conditions.

Risk for incident comorbidities, nonhepatic cancer and mortality in acute hepatic porphyria: A matched cohort study in 1244 individuals.

The acute hepatic porphyrias (AHP) are associated with long-term complications such as primary liver cancer, hypertension, and chronic kidney disease. Data on other related comorbidities are scarce. In this register-based, matched cohort study, we assessed the risks of nonhepatic cancers, cardiovascular diseases, renal diseases, psychiatric disorders, and mortality in relation to porphyria type, sex, and biochemical disease activity. All patients in the Swedish porphyria register with a verified AHP diagnosis during 1987-2015 were included. The biochemical activity of acute intermittent porphyria was assessed using recorded maximal urinary porphobilinogen (U-PBG). Data on incident comorbidities and mortality were collected from national health registries. Cumulative incidences, rates, and hazards were compared to reference individuals from the general population, matched 1:10 by age, sex, and county. We identified 1244 patients with AHP with a median follow-up of 19 years. Health registries identified 149 AHP-subjects (12.0%) with nonhepatic cancer, similar to 1601 (13.0%) in the matched reference population (n = 12 362). Patients with AHP had a higher risk of kidney cancer (0.8% vs. 0.2%, p < 0.001), hypertension, and chronic kidney disease but no increase in risk for cardiovascular disease, except for cerebrovascular disease in patients with elevated U-PBG, (aHR = 1.40 [95% CI:1.06-1.85]). Mortality risk during follow-up was higher among patients with AHP (21% vs. 18%, p = 0.001), and associated with primary liver cancer, female sex, and biochemical activity. In conclusion, AHP is associated with an increased risk of kidney cancer, hypertension, chronic kidney disease, and mortality but not with cardiovascular disease or other nonhepatic cancers.

Streamlining Genetic Diagnosis With Long-Range Polymerase Chain Reaction (PCR)-Based Next-Generation Sequencing for Type I and Type II Collagenopathies.

In the practice of clinical genetics, gene testing is usually guided by clinical diagnosis. When dealing with rare diseases, it is often necessary to create new test systems. The handling of a gene with a substantial number of exons poses a challenge both in sequential Sanger sequencing for each exon, and in the setup of capture probes to each exon for next-generation sequencing (NGS). We present very long amplicon sequencing (vLAS), an optimized long-range polymerase chain reaction (PCR)-based NGS method that overcomes this challenge. By utilizing approximately 20 Kb long PCR products and short-read NGS, vLAS is emerging as a highly adaptable and effective solution, especially for genes with numerous exons concentrated in a limited genomic region. Here, we demonstrate vLAS in the analysis of five patients with type I and two with type II collagenopathies. The integration of user-friendly NGS methods into genetic diagnosis enhances the practicality of clinical genetics.

Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene.

We present a patient with unusual episodes of muscular weakness due to homozygous deletion of exon 2 in the MICU1 gene. Forty-three patients from 33 families were previously described with homozygous and compound heterozygous, predominantly loss of function (LoF) variants in the MICU1 gene that lead to autosomal recessive myopathy with extrapyramidal signs. Most described patients developed muscle weakness and elevated CK levels, and half of the patients had progressive extrapyramidal signs and learning disabilities. Our patient had a few severe acute episodes of muscle weakness with minimal myopathy features between episodes and a strongly elevated Creatinine Kinase (CK). Whole exome sequencing (WES) was performed and the homozygous deletion of exon 2 was suspected. To validate the diagnosis, we performed an RNA analysis of all family members. To investigate the possible impact of this deletion on the phenotype, we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated MICU1 protein that could partly interact with MCU protein in a mitochondrial Ca2+ complex. We suspect that this unusual phenotype of the proband with MICU1-related myopathy could be explained by the presence of the truncated but partly functional protein. This work helps to define the clinical polymorphism of MICU1 deficiency better.

Family screening of hypertrophic cardiomyopathy in children: a case report.

Background: Paediatric hypertrophic cardiomyopathy (HCM) caused by sarcomere protein gene mutations is more common than previously thought. We present the case of a 9-year-old boy that was diagnosed with HCM during family screening. Case summary: We present a case of a 9-year-old boy with a family history of sarcomeric HCM who was diagnosed with hypertrophic obstructive cardiomyopathy (HOCM) during clinical screening. Echocardiography and cardiovascular magnetic resonance imaging revealed asymmetric left ventricular hypertrophy with a maximum wall thickness of 18-19 mm. Cardiovascular magnetic resonance late gadolinium enhancement imaging showed patchy fibrosis within the area of maximum wall thickness. Genetic testing confirmed the presence of the familial mutation in the MYL2 gene. The patient was started on bisoprolol. Furthermore, risk stratification was performed and a recommendation for implantable cardioverter-defibrillator implantation was made. Discussion: This case demonstrates that significant HCM can already start in childhood and discusses the recommendations for family screening on the basis of recently published studies and the present European Society of Cardiology guideline.

Congenital myopathy as a new phenotype caused by two undescribed variants in ASCC1 gene.

We present a patient with congenital myopathy and an inborn epiphysiolysis of the ulna. Whole-exome sequencing analysis revealed two novel mutations in Activation Signal Cointegrator Complex 1 (ASCC1) gene in a compound heterozygous state-a splicing variant c.395-2A>G and a deletion of the first two coding exons. Homozygous and compound heterozygous LoF variants in ASCC1 gene lead to a severe phenotype of spinal muscular atrophy with congenital bone fractures 2 (SMABF2). All patients described to date presented with a severe muscular hypotony, inborn fractures, and passed away shortly after birth while our proband had moderate hypotony, no fractures, but epiphysiolysis and he was 3.5 years old at the time of examination. To explain the phenotype of our patient, we performed an RNA analysis of all family members. We discovered that the c.395-2A>G variant results in two aberrant mRNA isoforms. We also validated the deletion of two exons in ASCC1 gene that lead to the increased expression of this truncated transcript by 1.8 times. To investigate the possible impact of this deletion on the phenotype we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated protein with shortened KH domain and a full RNA ligase-like domain. We suggest that this unexpectedly different phenotype of the proband with ASCC1-related disorder could be explained by the presence of the truncated protein with an increased expression.

Pathogenic variants carrier screening in New Brunswick: Acadians reveal high carrier frequency for multiple genetic disorders.

BACKGROUND: Founder populations that have recently undergone important genetic bottlenecks such as French-Canadians and Ashkenazi Jews can harbor some pathogenic variants at a higher carrier rate than the general population, putting them at a higher risk for certain genetic diseases. In these populations, there can be considerable benefit to performing ethnic-based or expanded preconception carrier screening, which can help in the prevention or early diagnosis and management of some genetic diseases. Acadians are descendants of French immigrants who settled in the Atlantic Coast of Canada in the seventeenth century. Yet, the Acadian population has never been investigated for the prevalence/frequency of disease-causing genetic variants. METHODS: An exome sequencing panel for 312 autosomal recessive and 30 X-linked diseases was designed and specimens from 60 healthy participants were sequenced to assess carrier frequency for the targeted diseases. RESULTS: In this study, we show that a sample population of Acadians in South-East New Brunswick harbor variants for 28 autosomal recessive and 1 X-linked diseases, some of which are significantly more frequent in comparison to reference populations. CONCLUSION: Results from this pilot study suggests a need for further investigation of genomic variation in this population and possibly implementation of targeted carrier and neonatal screening programs.

Musculoskeletal diseases in Marfan syndrome: a nationwide registry study.

BACKGROUND: Marfan syndrome is associated with abnormalities in the musculoskeletal system including scoliosis, pectus deformities, protrusio acetabuli, and foot deformities. Over a life span, many patients with Marfan syndrome will need treatment; however, the musculoskeletal morbidity over a life span is not well described. The aim of the present study was to assess the overall burden of musculoskeletal disease in patients with Marfan syndrome. MATERIALS AND METHODS: A registry-based, nationwide epidemiological study of patients with a Ghent II verified Marfan syndrome diagnosis from 1977 to 2014. Each patient was matched on age, and sex with up to 100 controls from the background population. RESULTS: We identified 407 patients with Marfan syndrome and 40,700 controls and compared their musculoskeletal diagnoses and surgical treatments using Cox proportional hazards ratio (HR). The risk of a registration of a musculoskeletal diagnosis in patients with Marfan syndrome was significantly increased compared to controls (HR: 1.94 (1.69-2.24). One out of six with Marfan syndrome was registered with scoliosis (HR: 36.7 (27.5-48.9). Scoliosis was more common in women with Marfan syndrome compared to men (HR: 4.30 (1.73-1.08)). One out of 11 were registered with a pectus deformity HR: 40.8 (28.1-59.3), and one out of six with a deformity of the foot. Primarily pes planus (HR: 26.0 (15.2-44.3). The proportion of patients with Marfan syndrome (94/407) that underwent musculoskeletal surgery was also significantly higher (HR: 1.76 (1.43-2.16)). The major areas of surgery were the spine, pectups correction, and surgery of the foot/ankle. Ten patients with Marfan syndrome had elective orthopedic surgery without being recognized and diagnosed with Marfan syndrome until later in life. None of these had scoliosis, pectus deformity or a foot deformity. Among patients with an aortic dissection, the age at dissection was 34.3 years in those with at least one major musculoskeletal abnormality. In patients without a major abnormality the age at dissection was 45.1 years (p < 0.01). CONCLUSIONS: The extent of musculoskeletal disease is quite significant in Marfan syndrome, and many will need corrective surgery during their life span. Surgeons should be aware of undiagnosed patients with Marfan syndrome when treating patients with a Marfan syndrome like-phenotype.

Novel detection of mutation in the TECPR2 gene in a Chinese hereditary spastic paraplegia 49 patient: a case report.

BACKGROUND: Hereditary spastic paraplegia 49 (HSP49) is an autosomal recessive genetic disease first discovered in 2012; and which the mutation primarily affects Bukharian Jewish patients. CASE PRESENTATION: The present case reports the first instance of HSP49 detected in China. The patient had normal mental development and good athletic ability before 10 years old and presented with instable temperature, mental retardation, spastic ataxia, and paroxysmal convulsions. Genetic diagnosis was based on detection of whole exons and two heterozygous variants in the exon region of the TECPR2 gene: c.1729C > T and c.4189G > A. Mutations at these two sites have not been previously reported. CONCLUSIONS: This case expands the gene mutation spectrum and clinical phenotypic characteristics of autosomal recessive HSP in China; moreover, it indicates differences in the clinical phenotype of HSP49 in different ethnicities. In addition, this reported provides further evidence regarding the effectiveness of targeted next-generation sequencing technology in improving the efficiency and diagnostic rate of genetic diagnosis of HSP.

Risk of primary liver cancer in acute hepatic porphyria patients: A matched cohort study of 1244 individuals.

BACKGROUND: The acute hepatic porphyrias (AHP) are associated with a risk of primary liver cancer (PLC), but risk estimates are unclear, and what AHP characteristics that predict PLC risk are unknown. In this register-based, matched cohort study, we assessed the PLC risk in relation to biochemical and clinical porphyria severity, genotype, age, and sex. METHODS: All patients in the Swedish porphyria register with acute intermittent porphyria (AIP), variegate porphyria (VP), or hereditary coproporphyria (HCP) during 1987-2015 were included. This AHP cohort was compared with age-, sex-, and county-matched reference individuals from the general population. National register-based hospital admissions for AHP were used to indicate the clinical severity. For AIP, the most common AHP type, patients were stratified by genotype and urinary porphobilinogen (U-PBG). Incident PLC data were collected from national health registers. RESULTS: We identified 1244 individuals with AHP (1063 [85%] AIP). During a median follow-up of 19.5 years, we identified 108 incident PLC cases, including 83 AHP patients (6.7%) and 25 of 12,333 reference individuals (0.2%). The adjusted hazard ratio for AHP-PLC was 38.0 (95% confidence interval: 24.3-59.3). Previously elevated U-PBG and hospitalizations for porphyria, but not AIP genotype or sex, were associated with increased PLC risk. Patients aged >50 years with previously elevated U-PBG (n = 157) had an annual PLC incidence of 1.8%. CONCLUSION: This study confirmed a high PLC risk and identified a strong association with clinical and biochemical AIP activity. Regular PLC surveillance is motivated in patients older than 50 years with a history of active AIP.

Whole body diffusion weighted imaging with background suppression in pachydermoperiostosis: a case report.

Hypertrophic osteoarthropathy (HOA) is a disease characterized by abnormal skin findings and bone deformities related to subperiosteal bone formation. The disease can be associated with major systemic manifestations (secondary form) or present with absent or less prominent systemic signs and symptoms (primary form). The primary form is called pachydermoperiostosis (PDP). Whole body diffusion weighted imaging with background suppression (WB-DWIBS) is a magnetic resonance imaging (MRI) technique that has been used to highlight whole body involvement in various entities by suppressing background body signals, and is commonly used in oncologic work-ups. In this paper, we present the case of a 23-year-old male presenting with normocytic anemia and coarse facial features, as well as biological anomalies, and we report the use of WB-DWIBS in establishing the patient's diagnosis of PDP.

A comparison of the clinical characteristics of pediatric urolithiasis patients with positive and negative molecular diagnoses.

PURPOSE: To compare the clinical characteristics of pediatric urolithiasis patients with positive and negative molecular diagnoses. METHODS: The clinical characteristics corresponding to pediatric urolithiasis patients that had undergone exome sequencing at our hospital between January 2016 and May 2021 were collected. Genetic analysis results were used to separate patients into positive and negative molecular diagnosis groups. Multivariate logistic regression analyses adjusted for visiting age, sex, ethnicity, province, and body mass index were used to compare differences in medical history, diagnostic imaging findings, and renal function between individuals with and without molecular diagnoses. RESULTS: In total, 194 patients with pediatric urolithiasis of unknown etiology underwent exome sequencing and were included in the present study, of whom 63 obtained urolithiasis-related molecular diagnoses. Relative to cases without a molecular diagnosis, those with a positive molecular diagnosis were more likely to be associated with a positive family history (OR 2.84, 95% CI 1.29-6.29, p = 0.008), consanguineous parents (OR 24.7, 95% CI 1.34-454, p = 0.002), early onset (OR 1.26, 95% CI 1.09-1.45, p < 0.001), nephrocalcinosis (OR 10.6, 95% CI 3.06-36.6, p < 0.001), cast stone (OR 18.9, 95% CI 4.40-81.1, p < 0.001), multiple stones (OR 13.9, 95% CI 6.39-30.2, p < 0.001), bilateral stones (OR 7.04, 95% CI 3.47-14.2, p < 0.001), a lower estimated glomerular filtration rate (OR 1.17, 95% CI 1.07-1.28, p < 0.001), and chronic kidney disease (OR 26.9, 95% CI 1.42-526, p < 0.001). CONCLUSION: A positive family history, consanguineous parents, early onset, nephrocalcinosis, severe stone burden, and impaired renal function are signals of concern that are suggestive of inherited urolithiasis.

Single Nucleotide Polymorphisms in Neonatal Necrotizing Enterocolitis.

The etiopathogenesis of necrotizing enterocolitis (NEC) remains unclear, but increasing information suggests that the risk and severity of NEC may be influenced by single nucleotide polymorphisms in many genes. In this article, we have reviewed gene variations that have either been specifically identified in NEC or have been noted in other inflammatory bowel disorders with similar histopathological abnormalities. We present evidence from our own peer-reviewed laboratory studies and data from an extensive literature search in the databases PubMed, EMBASE, and Scopus. To avoid bias in the identification of existing studies, search keywords were short-listed both from our own studies and from PubMed's Medical Subject Heading (MeSH) thesaurus.

Cellular mechanisms of connexin-based inherited diseases.

The 21-member connexin gene family exhibits distinct tissue expression patterns that can cause a diverse array of over 30 inherited connexin-linked diseases ranging from deafness to skin defects and blindness. Intriguingly, germline mutations can cause disease in one tissue while other tissues that abundantly express the mutant connexin remain disease free, highlighting the importance of the cellular context of mutant expression. Modeling connexin pathologies in genetically modified mice and tissue-relevant cells has informed extensively on no less than a dozen gain- and loss-of-function mechanisms that underpin disease. This review focuses on how a deeper molecular understanding of the over 930 mutations in 11 connexin-encoding genes is foundational for creating a framework for therapeutic interventions.