[Monogenic clinico-genetic units and pediatric practice].
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Congenital Abnormalities↗
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Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.
Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects. Of the subjects, 88.6% were included in a subgroup with high enzyme activity (13.50 +/- 1.86 U, mean +/- SD), 11.1% were included in a subgroup with intermediate activity (7.20 +/- 1.08 U), and 0.3% had undetectable activity. This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity, TPMT(L) and TPMT(H), with gene frequencies of .059 and .941, respectively. If RBC TPMT activity is inherited in an autosomal codominant fashion, then subjects homozygous for TPMT(H) would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMT(L) would have undetectable activity. The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families and among 35 members of two kindreds and one family selected because they included probands with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT. For example, in eight matings between subjects with intermediate activity (presumed genotype TPMT(L)TPMT(H)) and subjects with high activity (presumed genotype TPMT(H)TPMT(H)), 47% (8/17) of the offspring had intermediate activity. This value is very similar to the 50% figure expected on the basis of autosomal codominant inheritance (chi(2) ([1]) = .059). Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines.
Adult↗
[Genetic counseling in families with monogenic recessive metabolic diseases].
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Carbohydrate Metabolism, Inborn Errors↗
On mixtures of three normal populations caused by monogenic inheritance: application to desipramine metabolism.
For a mixture of three normal distributions, which represent genotypes AA, Aa and aa, a method of estimation of the seven unknown parameters is proposed which works well whenever the phenotype (aa) is sufficiently well separated from the phenotype (AA, Aa). It is based on p-values of Kolmogorov's test of goodness of fit to normality. Initial parameter values for this iterative algorithm can be found by visual check and/or by using the EM algorithm. In an example of a data set of size 59 from a study of the metabolic rate of desipramine, the usefulness of this method is demonstrated. Extensions to more complex situations are feasible and are indicated at the end.
Adolescent↗
International Federation of Clinical Chemistry (IFCC). Molecular biology techniques in the diagnosis of monogenic diseases.
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Female↗
[Monogenic hereditary diseases in Gorno-Mariĭskiĭ district of Mariĭ El republic].
The population of Gornomariiskii raion, Marii El Republic, primarily made up of mountain Marii, was subjected to medical genetic examination. The size of the entire population is 54853. Estimates of hereditary pathology in urban and rural populations of the raion were obtained. They were 0.68 and 1.11, respectively, for autosomal dominant pathology (AD); 0.55 and 0.81 for autosomal recessive pathology (AR); and 0.45 and 0.20 for X-linked pathology. Twenty-two, 25, and six nosologic forms of autosomal dominant, autosomal recessive, and X-linked diseases were revealed, respectively. We attempted to compare the sample under consideration with previously studied Russian and Finnish populations for rare pathologic recessive genes.
Ethnicity↗
Genetic study in psoriasis. 1. Checking of the possibility of monogenic inheritance of psoriasis.
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Child↗
[Use of variable number of tandem repeat polymorphism in assessing correct sampling in prenatal diagnosis of monogenic disorders].
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Amniocentesis↗
[The molecular genetic nature of the mutations responsible for the development in Ukraine of more widely spread forms of neuromuscular pathology and mental retardation with a monogenic nature of the heredity].
DNA-analysis of some mutation of SMN, dystrophin, FMR1 and PAH genes was performed among 149 high risk families of SMA, DMD, fragile X syndrome and PKU from different regions of Ukraine. The results of analysis of: deletions in the 7th and 8th exons of SMN gene; deletions in muscle-specific promoter region and 15 exons of dystrophin gene; R408W and IVS10nt546 mutations in PAH gene; GGG-expansions in FMR1 gene are presented.
DNA↗
[From monogenic to polygenic: model of Hirschsprung disease].
Hirschsprung's disease (HSCR, aganglionic megacolon) is a frequent congenital malformation regarded as a multigenic neurocristopathy. Three susceptibility genes have been recently identified in HSCR, namely the RET proto-oncogene, the endothelin B receptor (EDNRB) gene, and the endothelin 3 (EDN3) gene. RET gene mutations were found in significant proportions of familial (50%) and sporadic (15-20%) HSCR, while homozygosity for EDNRB or EDN3 mutations accounted for the rare HSCR-Waardenburg syndrome (WS) association. More recently, heterozygous EDNRB and EDN3 missense mutations have been reported in isolated HSCR patients. Some of these results were obtained after the identification of mouse genes whose natural or site-directed mutations resulted in megacolon and coat color spotting. There is also conclusive evidence for the involvement of other independent loci in HSCR. In particular, the recent identification of neurotrophic factors acting as RET ligands (GDNF and Neurturin) provide additional candidate genes for HSCR. The dissection of the genetic etiology of HSCR disease may then provide a unique opportunity to distinguish between a polygenic and a genetically heterogeneous disease, thereby helping to understand other complex disorders and congenital malformations hitherto considered as multifactorial in origin. Finally, the study of the molecular bases of HSCR is also a step towards the understanding of developmental genetics of the enteric nervous system giving support to the role of the tyrosine kinase and endothelin-signaling pathways in the development of neural crest-derived enteric neurons in human.
Animals↗
Polygenic Susceptibility in Peripartum, Alcohol-Induced, and Cancer Therapy-Related Cardiomyopathies.
IMPORTANCE: Rare monogenic variants linked to nonischemic dilated cardiomyopathy (DCM) are enriched among individuals with secondary cardiomyopathies, such as peripartum (PPCM), alcohol-induced (ACM), and cancer therapy-related (CCM) cardiomyopathies. However, it remains unclear whether a polygenic predisposition to DCM also contributes to these conditions. OBJECTIVE: To assess the association of a DCM polygenic score with PPCM, ACM, and CCM, and to evaluate the contributions of monogenic and polygenic susceptibilities to these secondary cardiomyopathies. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective genetic association analysis of data from the Mass General Brigham (MGB) Biobank (n = 42 137, 2008-2025), with replication in the UK Biobank (n = 295 160, 2005-2010), FinnGen (n = 417 950, 2017-2025), and the Veterans Affairs Million Veteran Program (n = 516 066, 2011-2025). In MGB Biobank, medical records were reviewed to ascertain secondary cardiomyopathy cases and antecedent clinical risk factors. EXPOSURES: DCM polygenic risk score and DCM monogenic variants. MAIN OUTCOMES AND MEASURES: The primary outcomes were the association of the DCM polygenic risk score with PPCM, ACM, and CCM and the prevalence of monogenic variants and a high polygenic score among individuals with cardiomyopathy. RESULTS: The mean (SD) age in the MGB Biobank was 55.7 (17.0) years at enrollment, and 24 551 (58.3%) were female. Across the 4 study cohorts, 3414 individuals with secondary cardiomyopathy were identified, including 70 with PPCM, 2281 with ACM, and 1063 with CCM. The DCM polygenic score was associated with PPCM (odds ratio [OR], 1.82 per SD; 95% CI, 1.43-2.30), ACM (OR, 1.56; 95% CI,1.34-1.82), and CCM (OR, 1.64; 95% CI,1.24-2.15) (all with P < .001). Monogenic variants were enriched but present in 7 of 113 individuals with medical record-reviewed cardiomyopathy in MGB, while 66 had a high polygenic score, which conferred an approximately 3-fold increased odds of cardiomyopathy. Most individuals with cardiomyopathy lacked antecedent clinical risk factors. CONCLUSIONS AND RELEVANCE: In this cohort study, individuals with PPCM, ACM, and CCM were enriched for monogenic DCM variants and a high DCM polygenic score, suggesting a shared genetic susceptibility influenced by distinct environmental precipitants. These findings support a shared genetic architecture between secondary cardiomyopathies and DCM, although additional work with larger numbers of individuals with cardiomyopathy is needed to confirm these findings.
Humans↗
Genetic background of neurological disorders with basal ganglia calcification.
BACKGROUND: Bilateral basal ganglia calcifications (BGCs), if severe, are known hallmarks for idiopathic BGC disease (IBGC), but if milder, are often considered radiological findings of unknown significance. In previous studies, only a minority of patients with BGC had monogenic forms of IBGC. METHODS: We studied consecutive patients from a tertiary neurology clinic with bilateral BGCs of variable severity, and their families. We analyzed known IBGC genes, and an extended panel of genes linked to monogenic stroke and metabolic conditions. Clinical, radiological, and genetic data were collected, including vascular risk factors, cerebrovascular events, imaging findings (total calcification score, white matter hyperintensities, ischemic/hemorrhagic lesions), and relevant family history. RESULTS: Twenty-four families with BGCs and neurological symptoms were analyzed. Disease-causing variants were identified in 14 families (58.3%). Eight patients had IBGC (variants in SLC20A2, PDGFB, MYORG), 4 had mitochondrial disease (MT-TL1), and 2 had monogenic vascular conditions (GAL, MAP3K6). Three variants were novel. BGC severity was highest in IBGC cases, while vascular and mitochondrial cases had milder calcifications. White matter hyperintensities were seen in 94.7% of cases and correlated highly with the total calcification score. Clinical vascular events had occurred in 41.7% cases. No monogenic cause was found in 10 patients, although many of these showed clinical or radiological features suggestive of monogenic disease. CONCLUSIONS: Bilateral BGCs can occur in many neurogenetic disorders apart from IBGCs, and a broader genetic search increases the diagnostic yield. Patients with BGCs frequently had clinical cerebrovascular events, which emphasizes the role of cerebrovascular pathology in BGCs.
Humans↗
Role and relevance of genetic testing in patients with kidney stones: a review from EAU Section of Endourology.
PURPOSE OF REVIEW: Kidney stones have a high heritability. More than 40 genes have been identified causing monogenic forms of kidney stone disease (KSD). Kidney stone formers with genetic variants implicated in monogenic forms of KSD often suffer from early onset, high recurrence rates, and chronic kidney disease. Some patients may also exhibit extrarenal disease requiring attention. RECENT FINDINGS: Recent analysis of KSD patients identified a likely monogenic cause in pediatric populations in 17-30% of participants while in adult unselected populations 2.7-8% had a positive finding. More patients carry single genetic variants in monogenic forms that are classically considered as autosomal recessive but may cause an intermediate genetic risk for the development of KSD possibly in interaction with environmental or lifestyle factors. Genome-wide association studies have identified additional risk loci associating with KSD. Their clinical relevance are currently investigated. Patients with recurrent kidney stone episodes may be at elevated risk of progressive chronic kidney disease. SUMMARY: Monogenic causes of KSD are prevalent in patients less than 25 years of age and in some patients with high-risk metabolic profiles. These patients should undergo genetic testing to enable a precise molecular genetic diagnosis and personalized therapy as well as family counseling and screening.
Humans↗
Single gene disorders causing ischaemic stroke.
Stroke is the third most common cause of death and the leading cause of long-term neurological disability in the world. Conventional vascular risk factors for stroke contribute approximately to only forty to fifty percent of stroke risk. Genetic factors may therefore contribute to a significant proportion of stroke and may be polygenic, monogenic or multi-factorial. Monogenic (single gene) disorders may potentially account for approximately one percent of all ischaemic stroke. Monogenic stroke disorders include conditions such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS). In addition, other monogenic conditions such as sickle cell and Fabry disease also lead to stroke. These monogenic disorders cause either small vessel or large vessel stroke (or a combination of both) and serve as useful models for understanding and studying conventional stroke and cerebrovascular disease and its accompaniments such as vascular dementia.
Genetic Diseases, Inborn↗
The assessment of Achilles tendon size in primary hypercholesterolaemia by computed tomography.
The Achilles tendons of 43 men and women were examined by conventional radiography and by computed tomography (CT). Eleven subjects were normolipidaemic and 32 had familial hypercholesterolaemia, of whom 19 were considered to have polygenic hypercholesterolaemia and 13 monogenic. Achilles tendon xanthomata were identifiable by both radiography and CT. In assessing the size of xanthomata, CT had advantages since the junction between muscle and tendon was easily identified and all the dimensions and the cross-sectional area of the tendon could be measured. The area of Achilles tendons was closely correlated with body height in normolipidaemic men and women and patients with polygenic hypercholesterolaemia. In monogenic hypercholesterolaemia this relationship was lost. The tendons of the normolipidaemic group and of patients with polygenic hypercholesterolaemia were indistinguishable, whereas those of patients with monogenic hypercholesterolaemia were significantly larger. Neither the maximum nor the average CT attenuation values of the tendons differed significantly between the 3 groups. Of the patients with monogenic hypercholesterolaemia, those whose Achilles tendons were less than 200 mm2 in area had received treatment longer than those with larger tendons. CT shows promise as a means of assessing the therapeutic response of patients with monogenic familial hypercholesterolaemia.
Achilles Tendon↗
Genetics of type 2 diabetes mellitus.
The clinical picture of type 2 diabetes mellitus (T2DM) is formed by impairment in insulin secretion and resistance to insulin action. As a result of intensive efforts of the scientists around the world mutations and polymorphisms in a number of genes were linked with monogenic and polygenic forms of T2DM. Two major strategies were used in this research: genome scanning and the candidate gene approach. Monogenic forms, despite their rarity, constitute a field where substantial progress has been made in the dissection of the molecular background of T2DM. Monogenic forms of T2DM with profound defect in insulin secretion include subtypes of maturity onset diabetes of the young (MODY), maternally inherited diabetes with deafness (MIDD) caused by mitochondrial mutations, and rare cases resulting from insulin gene mutations. The majority of proteins associated with MODY are transcription factors, such as hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), HNF-1beta, and NEUROD1. They influence expression of the other genes through regulation of mRNA synthesis. Only MODY2 form is associated with glucokinase, a key regulatory enzyme of the beta cell. There are striking differences in the clinical picture of MODY associated with glucokinase and MODY associated with transcription factors. Three monogenic forms of T2DM characterized by severe insulin resistance are the consequence of mutations in the PPARgamma, ATK2, and insulin receptor genes. Patients with monogenic T2DM, particularly with MODY, sometimes, develop discrete extra-pancreatic phenotypes; for example, lipid abnormalities or a variety of cystic renal diseases. Efforts aiming to identify genes responsible for more common, polygenic forms of T2DM were less effective. These forms of T2DM have a middle/late age of onset and occur with both impaired insulin secretion and insulin resistance. Their clinical picture is created by the interaction of environmental and genetic factors, such as frequent polymorphisms of many genes, not just of one. These polymorphisms may be localized in the coding or regulatory parts of the genes and are present, although with different frequencies, in T2DM patients as well as in healthy populations. Sequence differences in a few genes have been associated, so far, with complex, polygenic forms of T2DM, for example, calpain 10, PPARgamma, KCJN11, and insulin. In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. It is expected that in the nearest future more T2DM susceptibility genes will be identified.
Diabetes Mellitus, Type 2↗
Multisite neural tube closure in humans.
We present evidence for multisite NT closure in humans with representative examples of types of NTDs that would be expected if NT closure in humans is similar to experimental mice models. We determine that the majority of NTDs can be classified by the multisite closure model. Further evidence for multisite closure of the NT is apparent in previous epidemiological studies, recognized monogenic disorders, and environmental and teratogenic exposures. Previous reliance on the single-site closure model has resulted in grouping of anomalies, obscuring evidence for multisite NT closure, etiological heterogeneity, varying recurrence risks, and site-specific effects of environmental factors. The NTDs have been previously referred to as being multifactorial, due to multiple genes and environmental factors. Etiological heterogeneity has been demonstrated previously as well. Classification of NTDs by closure site will be beneficial in better defining etiologies and environmental susceptibilities. Similarly, it is apparent to us that genetic variations in closure sequence, rate, and location are most likely monogenic and result in affected embryos being more susceptible to specific environmental factors, such as the effect of folic acid deficiency. Individual closure sites are most likely under the control of specific embryonically expressed genes, whose monogenic nature may not be apparent postnatally. For the disorders such as Meckel-Gruber syndrome and Walker-Warburg syndrome, the monogenic etiology for NTDs in affected individuals is apparent because of associated malformations. There are three important implications of this study: The first is that monogenic mouse models will be helpful in investigating the pathogenesis of NTDs in humans. The homologies between the mouse and human genome may allow linkage studies to be done in some families who have recurrence of NTDs. Second, in order to have useful results from studies of NTDs, NT anomalies need to be accurately described, either by the classical nomenclature (eg, meroacranium) or by referring to the corresponding closure site involvement (eg, closure 2 defect). Special attention needs to be addressed to those NTDs that do not appear to fit into a discrete closure site (eg, midthoracic spina bifida cystica) or laterally displaced NTDs, since they may be due to other etiologies. With improved nutrition, particularly folic acid treatment, specific etiologies for the remaining NTDs may become more apparent. Finally, recurrence risks for NTDs may vary between families based on the closure site affected, and whether or not associated anomalies are present.
Animals↗
Obtaining a Diagnostic Yield via Scan findings prior to the introduction of SEquencing retrospectivelY (ODYSSEY): a cohort study.
OBJECTIVE: To determine the retrospective yield of prenatal exome sequencing (PES) by establishing the proportion of children with a postnatal monogenic diagnosis that could have been diagnosed prenatally if PES had been available. METHODS: The study cohort comprised a sample of children in Northern Ireland, born between January 2010 and January 2018 (predating routine availability of PES), who received a monogenic diagnosis postnatally via next generation sequencing as part of either of two UK-wide studies (the 100 000 Genomes Project (2015-2018) or the Deciphering Developmental Disorders study (2011-2015)). Clinical data were collected retrospectively and correlated with the current UK National Health Service PES protocol, including the phenotypic eligibility criteria for PES and the associated fetal anomalies gene panel. Cases were considered retrospective diagnoses if the fetal phenotype would have been eligible for PES and the diagnostic gene was included on the test panel, meaning prenatal diagnosis in this current era could have been feasible. RESULTS: Of 101 children, 17.8% (95% CI, 10.3-25.3%) had both an eligible fetal structural anomaly (FSA) (i.e. high-risk FSA) and a diagnostic gene on the associated test panel, meaning that they could have been diagnosed prenatally in the current clinical landscape. The median length of the diagnostic odyssey for this subgroup of children was 3.7 years (1354 (range, 822-2450) days). Moreover, 58.4% (n = 59) of cases had no anomalies detected prenatally and 19.8% (n = 20) had a FSA that would not meet the eligibility criteria for PES (low-risk FSA). Although these cases would have been ineligible for PES under the current clinical pathway, 89.9% (n = 71/79) were affected by severe or profound syndromes. Postnatally, the most common functional anomalies were neurodevelopmental delay/intellectual disability and/or behavioral abnormality, which were observed in 80.2% (n = 81) of the included children. However, 80.2% (n = 65/81) of these affected children did not present with fetal anomalies eligible for PES. CONCLUSIONS: Almost one-fifth of children with a monogenic condition included in this study could have received a diagnosis via modern PES, avoiding a diagnostic odyssey lasting almost 4 years. However, despite having a monogenic condition, over half of the children did not present with any structural anomalies in utero. This demonstrates the degree to which fetal imaging is limited in its ability to reassure parents of the absence of a fetal genetic syndrome. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Humans↗