Monogenic Syndromes Research Articles

DNA methylation analysis for screening and diagnostic testing in neurodevelopmental disorders.

DNA methylation (mDNA) plays an important role in the pathogenesis of neurodevelopmental disorders (NDDs), however its use in diagnostic testing has been largely restricted to a handful of methods for locus-specific analysis in monogenic syndromes. Recent studies employing genome-wide methylation analysis (GWMA) have explored utility of a single array-based test to detect methylation changes in probands negative by exome sequencing, and to diagnose different monogenic NDDs with defined epigenetic signatures. While this may be a more efficient approach, several significant barriers remain. These include non-uniform and low coverage of regulatory regions that may have CG-rich sequences, and lower analytical sensitivity as compared with locus-specific analyses that may result in methylation mosaicism not being detected. A major challenge associated with the above technologies, regardless of whether the analysis is locus specific or genome wide, is the technical bias introduced by indirect analysis of methylation. This review summarizes evidence from the most recent studies in this field and discusses future directions, including direct analysis of methylation using long-read technologies and detection of 5-methylcytosine (5-mC or total mDNA) and 5-hydroxymethylacytosine (5-hmC) as biomarkers of NDDs.

Impact on Clinical Decision Making of Next-Generation Sequencing in Pediatric Epilepsy in a Tertiary Epilepsy Referral Center.

Background. Next-generation sequencing (NGS) describes new powerful techniques of nucleic acid analysis, which allow not only disease gene identification diagnostics but also applications for transcriptome/methylation analysis and meta-genomics. NGS helps identify many monogenic epilepsy syndromes. Pediatric epilepsy patients can be tested using NGS epilepsy panels to diagnose them, thereby influencing treatment choices. The primary objective of this study was to evaluate the impact of genetic testing on clinical decision making in pediatric epilepsy patients. Methods. We completed a single-center retrospective cohort study of 91 patients (43 male) aged 19 years or less undergoing NGS with epilepsy panels differing in size ranging from 5 to 434 genes from October 2013 to September 2017. Results. During a mean time of 3.6 years between symptom onset and genetic testing, subjects most frequently showed epileptic encephalopathy (40%), focal epilepsy (33%), and generalized epilepsy (18%). In 16 patients (18% of the study population), "pathogenic" or "likely pathogenic" results according to ACMG criteria were found. Ten of the 16 patients (63%) experienced changes in clinical management regarding their medication and avoidance of further diagnostic evaluation, that is, presurgical evaluation. Conclusion. NGS epilepsy panels contribute to the diagnosis of pediatric epilepsy patients and may change their clinical management with regard to both preventing unnecessary and potentially harmful diagnostic procedures and management. Thus, the present data support the early implementation in order to adopt clinical management in selected cases and prevent further invasive investigations. Given the relatively small sample size and heterogeneous panels a larger prospective study with more homogeneous panels would be helpful to further determine the impact of NGS on clinical decision making.

A Systematic Clinical Review of Prenatally Diagnosed Tetrasomy 9p.

Tetrasomy 9p was first described in 1973 and approximately 68 cases with a variable phenotype have been reported to date with 22 of them being detected prenatally. The objective of this study was to review prenatally-reported cases of tetrasomy 9p thus far and to identify ultrasound phenotypes that may be suggestive of this specific syndrome. A PubMed database search was done in February 2018 without any restriction of publication date orjournals, with the use of the following keywords: tetrasomy 9p, tetrasomy 9p prenatal, mosaic tetrasomy 9p, mosaic tetrasomy 9p prenatal, isochromosome 9p, duplication 9p prenatal, trisomy 9p prenatal. Reported cases were included if the clinical presentation and diagnostic approach of each case was clearly described. The most common characteristics of prenatally-detected tetrasomy 9p are intrauterine growth retardation (IUGR, 57.0%), central nervous system (CNS) abnormalities (59.0%), skeletal anomalies (29.0%), genitourinary and renal anomalies (29.0%) and cardiac defects (29.0%). The phenotypic spectrum of tetrasomy 9p is rather unspecific as these findings are commonly associated with other chromosome anomalies, as well as microdeletion/microduplication or monogenic syndromes. The combination of early fetal morphology and diagnostic genetic testing enables a definite tetrasomy 9p diagnosis and effective further pregnancy management.

A rare case of Cohen syndrome and early infantile epileptic encephalopath y (type 52) in two-year-old girl

The authors presented short review of Russian and foreign literature and clinical case of the girl with a rare monogenic disease Cohen syndrome and early infantile epileptic encephalopathy. Problems of differential diagnosis of Cohen syndrome with other neuro-oculocutaneous diseases are analyzed.

How I approach hereditary cancer predisposition in a child with cancer.

Approximately 10% of all children with cancer are affected by a monogenic cancer predisposition syndrome. This has important implications for both the child and her/his family. The assessment of hereditary cancer predisposition is a challenging task for clinicians and genetic counselors in daily routine. It includes consideration of tumor genetics, specific features of the patient, and the medical/family history. To keep up with the pace of this rapidly evolving and increasingly complex field of genetic susceptibility, we suggest a systematic approach for the evaluation of the child with cancer and her/his family by an interdisciplinary team specialized in hereditary cancer predisposition.

Neutrophilic Dermatoses and Their Implication in Pathophysiology of Asthma and Other Respiratory Comorbidities: A Narrative Review.

Neutrophilic dermatoses (ND) are a polymorphous group of noncontagious dermatological disorders that share the common histological feature of a sterile cutaneous infiltration of mature neutrophils. Clinical manifestations can vary from nodules, pustules, and bulla to erosions and ulcerations. The etiopathogenesis of neutrophilic dermatoses has continuously evolved. Accumulating genetic, clinical, and histological evidence point to NDs being classified in the spectrum of autoinflammatory conditions. However, unlike the monogenic autoinflammatory syndromes where a clear multiple change in the inflammasome structure/function is demonstrated, NDs display several proinflammatory abnormalities, mainly driven by IL-1, IL-17, and tumor necrosis factor-alpha (TNF-a). Additionally, because of the frequent association with extracutaneous manifestations where neutrophils seem to play a crucial role, it was plausible also to consider NDs as a cutaneous presentation of a systemic neutrophilic condition. Neutrophilic dermatoses are more frequently recognized in association with respiratory disorders than by chance alone. The combination of the two, particularly in the context of their overlapping immune responses mediated primarily by neutrophils, raises the likelihood of a common neutrophilic systemic disease or an aberrant innate immunity disorder. Associated respiratory conditions can serve as a trigger or may develop or be exacerbated secondary to the uncontrolled skin disorder. Physicians should be aware of the possible pulmonary comorbidities and apply this knowledge in the three steps of patients' management, work-up, diagnosis, and treatment. In this review, we attempt to unravel the pathophysiological mechanisms of this association and also present some evidence for the role of targeted therapy in the treatment of both conditions.

Gillespiе syndrome, caused by previously undescribed mutation in the gene <i>ITPR1<i>

Gillespie syndrome is one of the rare monogenic syndromes characterized by a combination of congenital muscular hypotonia, delayed psychomotor and speech development, ataxia and hypoplasia of the iris. The cause of disease – homozygous, compound heterozygous and heterozygous mutations in the gene ITPR1.We described a case history of a child of 1 year and 8 months whose parents were complaining of severe delay in psychomotor and speech development, and a violation of the functions of the visual analyzer. Neurological and ophthalmologic examinations were performed according to a standard procedure. Search for mutations was carried out using high-performance exome sequencing on NextSeg 500 (Illumina, USA) with an average coverage of at least 70–100x.Clinical and genetic characteristics of the patient with Gillespie syndrome due to the newly identified heterozygous missense mutation are presented. Mutation 1865T˃S in the 18 exon of the ITPR1 gene was found during the new generation sequencing of the exome. In the future, these data can be used to predict the characteristics of clinical manifestations and the severity of Gillespie syndrome, when a similar nucleotide substitution will be found in other patients.

MCC950 closes the active conformation of NLRP3 to an inactive state.

NLRP3 is an innate immune sensor contributing to the development of different diseases including monogenic autoinflammatory syndromes, gout, atherosclerosis, and Alzheimer’s disease. The molecule sulfonylurea MCC950 is a NLRP3 inflammasome inhibitor with potential clinical utility. However, the mechanism of action of MCC950 remains unknown. Here, we characterize the mechanism of action of MCC950 in both wild-type and autoinflammatory-related NLRP3 mutants, demonstrating that MCC950 closes the ‘open’ conformation of active NLRP3.

SAT-241 Hyposplenism and Autoimmune Hepatitis: Rare Complications of Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dystrophy (APECED)

Background: APECED is a rare monogenic autosomal recessive syndrome caused by mutation in the AIRE gene located on chromosome 21q22.3. Phenotypic expression is variable but classically includes chronic mucocutaneous candidiasis, chronic hypoparathyroidism and hypoadrenalism. Studies demonstrate prevalence of autoimmune hepatitis (AIH) is 12%, and hyposplenism is approximately 20%. (Peterson P, Pitkänen J, Sillanpää N,2004; Capalbo D, De Martino L, Giardino G, 2012) Clinical Case: A 29 year old man was diagnosed with autoimmune hepatitis (AIH) at 6 years. He presented with symptomatic hypocalcaemia secondary to autoimmune hypoparathyroidism at 11 years. At 12 years he developed primary adrenal insufficiency. He also had nail dystrophy and mucocutaneous candidiasis. Genetic analysis revealed he was homozygous for for a 13bp deletion in Exon 8 of the AIRE gene consistent with diagnosis of APECED. His sister, who presented with hypoparathyroidism, was also AIRE gene positive. He transitioned from paediatric to adult care age at 16 years and subsequently defaulted from care. Following re-engagement with adult services at age 19 years, he was diagnosed with cirrhosis and portal hypertension and has had an oesophageal variceal bleed. Regular dental review has not revealed an oral mucocutaneous malignancy. At age 24, during an admission with decompensated liver disease, an elevated LDH 384 I.U. /l (120 - 220) and bilirubin (total) 121 μmol/l (5-24) were noted. A blood film demonstrated Howell Jolly bodies, target cells, polychromasia, target cells and anisopoikilocytosis consistent with hyposplenism. In 2011 a CT abdomen reported the spleen as severely shrunken. On review of previous abdominal ultrasounds reports in dating back to 2012 the spleen was undetectable. He was therefore diagnosed with functional hyposplenism. Hyposplenism was complicated by streptococcal sepsis. He was treated as per guidelines with pneumococcus, haemophilus, meningitis C, influenza vaccinations and penicillin prophylaxis. The pathogenesis underlying functional hyposplenism in APECED is unknown however it is hypothesized that it occurs secondary to local AIRE gene dysfunction in the spleen.(Starzyk J, Kumorowicz-Kopiec M, Kowalczyk M, 2001). Another possible contributory factor in this gentleman is his liver cirrhosis. Discussion: This case highlights the multifaceted nature of this rare disease as well as the associated morbidity and need for a multidisciplinary approach to a complex multi-organ condition. It is important to be cognisant of its many associations in order to avoid missing life threatening diagnoses. Patients with APECED should be evaluated for hyposplenia and appropriate vaccination schedule initiated.

APOL1 risk genotype in Europe: Data in patients with focal segmental glomerulosclerosis and after renal transplantation

Apolipoprotein L1 (APOL1) risk variants are strongly associated with sporadic focal segmental glomerulosclerosis in populations with African ancestry. We determined the frequency of G1/G2 variants in patients with steroid-resistant nephrotic syndrome/focal segmental glomerulosclerosis with African or French West Indies origin in France and its relationships with other steroid-resistant nephrotic syndrome genes. In a cohort of 152 patients (139 families), the APOL1 risk variants were genotyped: the two risk allele (high risk) genotype was found in 43.1% of subjects compared to 18.9% in a control population (P<0.0001). Compared to patients in the low risk group, patients in the high-risk group were more likely to originate from French West Indies than from Africa. APOL1 high-risk genotype was more frequent in young adult patients, but it was also found in children and it was associated with a bad renal prognosis. APOL1 high-risk genotype was usually not associated with other causative mutation in known monogenic steroid-resistant nephrotic syndrome genes and families in which multiple individuals have focal segmental glomerulosclerosis may have APOL1-associated disease. After renal transplantation, recipients of deceased-donor kidney transplantation from individuals with recent African ancestry possessing two APOL1 high-risk variants have slightly shorter allograft survival. Effects of APOL1 are independent of other traditional risk factors. Recently it was shown that black living kidney donors homozygous for APOL1 high-risk alleles have significantly lower glomerular filtration rate and increased risk of end-stage renal disease after donation. However, APOL1 genotype may not summarize by itself the totality of this risk. We showed that living kidney donors of African ancestry in France with low-risk APOL1 genotype have lower postdonation eGFR increase and lower baseline kidney volume compared to Caucasian donors.

Atypical familial dysbetalipoproteinemia associated with high polygenic cholesterol and triglyceride scores treated with ezetimibe and evolocumab

We present a 37-year-old man diagnosed with familial dysbetalipoproteinemia who presented with the severe hyperlipidemic phenotype. None of the usual metabolic triggers were found to explain his severe lipid abnormalities. Genetic analysis revealed the expected APOE E2/E2 genotype, but no other mutations were found to explain any monogenic dyslipidemia or syndrome. Polygenic risk scores for quantitative lipid traits did reveal scores placing the patient in the >99th percentile for the general population concerning polygenic susceptibility for both high cholesterol and triglycerides. Owing to his gastrointestinal intolerance to two high-intensity statins, he was treated with both ezetimibe 10 mg a day and evolocumab 140 mg subcutaneously every 2 weeks. All measures of potentially atherogenic lipids were markedly improved and remained so for more than 10 months of follow-up. This case report shows an unusual trigger for severe hyperlipidemia with familial dysbetalipoproteinemia and a favorable therapeutic response to the combination of ezetimibe and evolocumab.

Type 1 Diabetes in STAT Protein Family Mutations: Regulating the Th17/Treg Equilibrium and Beyond.

Improvements in the immunological, molecular, and genetic technologies such as next-generation sequencing have led to an exponential increase in the number of monogenic immune dysregulatory syndromes diagnosed, where type 1 diabetes (T1D) forms part of the autoimmune manifestations. Here, we reviewed the mutations in the signal transducer and activator of transcription (STAT) protein family, namely gain-of-function (GOF) mutations in STAT1 and STAT3 as well as STAT5b deficiency, that show strong association to T1D susceptibility. The equilibrium of T-helper 17 (Th17) and regulatory T cells (Tregs) is often found altered in patients affected by STAT GOF mutations. While the increased number of Th17 cells and the concomitant decrease in Treg cells may explain T1D in STAT3 GOF patients, the reduced number of Th17 cells found in those carrying STAT1 GOF mutations added a new level of complexity on the exact role of Th17 in the pathogenesis of T1D. Here, we describe the possible mechanisms through which STAT3 and STAT1 GOF mutations may perturb the fate and function of Th17 and Tregs and explore how this may lead to the development of T1D. We propose that the study of monogenic diseases, and in particular STAT mutations, may not only improve our understanding of the function of the human immune system but also shed light onto the pathogenic mechanisms of T1D and the genetic variants that confer predisposition to the disease.

New autoinflammatory diseases.

Advances in sequencing techniques and systematic cohort-analysis of patients with autoinflammatory phenotypes have enabled a burst in the recognition of new autoinflammatory diseases and contributed to the description of the mechanisms involved in autoinflammation. This review focuses on new genetic and mechanistic discoveries that have broadened the definition of autoinflammatory diseases in the context of the established landscape, providing new therapeutic opportunities and avenues for further discoveries. Mechanistic insights of inflammatory diseases open opportunities for new targeted therapies. Advances in high-throughput screening of small-molecule inhibitors accelerate the discovery of new and more specific therapeutic options. Recent evidence establishes IL-18 as a driver of macrophage activation, emerging as a new biomarker and therapeutic target. Finally, the identification of escape of nonsense-mediated decay as the genetic mechanism resulting in a monogenic immune-dysregulatory disease, unveils a possibility for future discoveries. Recent mechanistic findings in autoinflammatory diseases as well as the identification of specific biomarkers and discovery of new diseases, continue to pave the way for ever more specific targeted approaches. These therapies are not only applicable to monogenic autoinflammatory syndromes but also for other diseases in which the same pathways are dysregulated.

Clinical and genetic characteristics of new allele variants of the Mowat–Wilson syndrome caused by ZEB2 gene mutations

To date, a large number of monogenic diseases and syndromes, in the clinical picture of which there are convulsions, a psycho-speech development delay and dysmorphic features have been described. One of the hereditary syndromes with a specific phenotype is the Movat–Wilson syndrome. To diagnose the syndrome, a set of survey methods was used: genealogical analysis, neurological examination, evaluation of intellectual development with the help of psychological tests, and sequencing of the new generation exome. As a result of sequencing exome on the panel of genes responsible for the emergence of hereditary epilepsy, two patients of different sex at the age of 10 and 5 years were identified with previously not described mutations in the ZEB2 gene in the heterozygous state. Clinical manifestations of the disease in these patients were of varying degrees of severity, which can be explained in terms of the functional significance of the changes detected. The variety of clinical manifestations of the same disease leads to considerable difficulties in diagnosing, however, due to the introduction of the nextgeneration sequencing in medical practice, the effectiveness of diagnosing hereditary diseases and syndromes, the verification of which has been difficult for a long time, has increased significantly.

Loss of complex O-glycosylation impairs exocrine pancreatic function and induces MODY8-like diabetes in mice

Cosmc is ubiquitously expressed and acts as a specific molecular chaperone assisting the folding and stability of core 1 synthase. Thus, it plays a crucial role in the biosynthesis of O-linked glycosylation of proteins. Here, we show that ablation of Cosmc in the exocrine pancreas of mice causes expression of truncated O-glycans (Tn antigen), resulting in exocrine pancreatic insufficiency with decreased activities of digestive enzymes and diabetes. To understand the molecular causes of the pleiotropic phenotype, we used Vicia villosa agglutinin to enrich Tn antigen-modified proteins from Cosmc-KO pancreatic lysates and performed a proteomic analysis. Interestingly, a variety of proteins were identified, of which bile salt-activated lipase (also denoted carboxyl-ester lipase, Cel) was the most abundant. In humans, frameshift mutations in CEL cause maturity-onset diabetes of the young type 8 (MODY8), a monogenic syndrome of diabetes and pancreatic exocrine dysfunction. Here, we provide data suggesting that differentially O-glycosylated Cel could negatively affect beta cell function. Taken together, our findings demonstrate the importance of correct O-glycan formation for normal exocrine and endocrine pancreatic function, implying that aberrant O-glycans might be relevant for pathogenic mechanisms of the pancreas.

Monogenic polyautoimmunity in primary immunodeficiency diseases.

Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency.

Glucose Homeostasis and Energy Balance in Children With Pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is a rare genetic disorder characterized by early-onset obesity and multihormone resistance. To treat abnormal weight gain and prevent complications such as diabetes, we must understand energy balance and glucose homeostasis in PHP types 1A and 1B. The aim of this study was to evaluate food intake, energy expenditure, and glucose homeostasis in children with PHP. Assessments included resting energy expenditure (REE), physical activity, food intake, sucrose preference, questionnaires, endocrine status, and auxological status. All patients underwent an oral glucose tolerance test (OGTT). Vanderbilt University Medical Center. We assessed 16 children with PHP1A, three with PHP1B, and 15 healthy controls. Food intake during an ad lib buffet meal and glucose at five time points during OGTT. PHP1A and control groups were well matched. Participants with PHP1A had significantly lower REE without concomitant change in food intake or physical activity. At baseline, participants with PHP1A had significantly lower fasting glucose and insulin resistance. During OGTT, participants with PHP1A had significantly delayed peak glucose and a slower rate of glucose decline despite similar oral glucose insulin sensitivity. Participants with PHP1A had 0.46% lower HbA1c levels than controls from a clinic database after adjustment for OGTT 2-hour glucose. The PHP1B group was similar to the PHP1A group. In contrast to other monogenic obesity syndromes, our results support reduced energy expenditure, not severe hyperphagia, as the primary cause of abnormal weight gain in PHP. Patients with PHP are at high risk for dysglycemia without reduced insulin sensitivity.

Genetics of Lipodystrophy: Can It Help in Understanding the Pathophysiology of Metabolic Syndrome?

Understanding phenotypes and their genetic determinants for metabolic syndrome (MetS) has been quite challenging. With the advent of systems genomic approaches, there is a need to decipher methods for identification and evaluating the functional role of phenotypic traits associated with complex diseases, such as MetS. The monogenic syndromes of lipodystrophy are well understood, but the molecular pathophysiology of insulin resistance (IR) underpinning the obesity, diabetes mellitus, and dyslipidemia is not well deciphered. In this commentary, we argue the role of pathophysiology of MetS, and its effects into possible understanding of genetic determinants associated with lipodystrophy-mediated diabetes mellitus.

Hereditary syndromes associated with the congenital heart diseases in Azerbaijan

This article is devoted to the study of the incidence and structure of the genetic syndromes associated with congenital heart diseases in Azerbaijan. The results of observation of 430 children with congenital heart diseases, which have been stayed in the Child Department of Scientific Surgery Center named after Academician M.A. Topchubashov during 2010-2015 period, have been analyzed. It was demonstrated that the incidence of the chromosomal and monogenic pathological conditions is 6.5±1.2% (28 children) among the above population. The chromosomal syndromes were diagnosed in 20 (4.7±1.0%) children, monogenic ones – in 8 (1.9+0.7%) children. The chromosomal pathological condition was mostly presented with the Down’s syndrome (in 12 patents). As to the monogenic syndromes, it was mostly the heterotoxic syndrome (4 children). These data testify that in spite of the multifactorial genesis of the most of the congenital heart diseases and role of the unfavorable factors of the antenatal period, the genetic component influences with a great importance upon the prevalence rate of the malformations.

Elucidating the genetics of craniofacial shape.

Alterations in craniofacial size and shape are apparent in many monogenic diseases and syndromes, but remarkably little is known about the genetics of face shape within healthy populations. This may be set to change following publication of a study that combines unsupervised hierarchical spectral clustering and canonical correlation analysis to help identify common genetic variants associated with craniofacial shape.