The authors present a case of 1st trimester miscarriage where an early, complete hydatidiform mole was clinically suspected. Histopathological and immunohistochemical analyses excluded a complete mole, but the histomorphological profile was in concordance with a partial hydatidiform mole. Genetic analysis excluded a partial mole based on biparental genome composition, where further genetic analyses detected trisomy of chromosome 16. Trisomy of chromosome 16 is a frequent cause of 1st trimester abortions and may lead to highly abnormal placental histomorphology mimicking a partial mole. Genetic analyses are crucial for proper differential diagnosis and for the determination of adequate follow-up and prognosis for further pregnancies.

• Klíčová slova
• Aneuploidy, DNA analysis, placental histomorphology, trisomy 16,
• MeSH
• diferenciální diagnóza MeSH
• dospělí MeSH
• lidé MeSH
• lidské chromozomy, pár 16 * genetika   MeSH
• mola hydatidosa * genetika   diagnóza   patologie   MeSH
• mozaicismus MeSH
• nádory dělohy * genetika   diagnóza   patologie   MeSH
• první trimestr těhotenství MeSH
• samovolný potrat genetika   diagnóza   MeSH
• těhotenství MeSH
• trizomie * diagnóza   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

A case of double trisomy 16 and 22 in the second pregnancy loss is presented. DNA analyses (short tandem repeats genotyping) of miscarriage specimen was indicated because of ultrasound suspicion of partial hydatidiform mole. After the partial hydatidiform mole exclusion, further DNA analyses focused on the most common aneuploidies causing pregnancy loss, detected double trisomy 16 and 22 in the product of conception. The couple was referred to clinical genetic consultation and normal parental karyotypes were proved. For further explanatory purposes, archived material from the first pregnancy loss was analyzed and trisomy of chromosome 18 was detected. By comparison of allelic profiles of the mother, father, and both losses, the maternal origin of all aneuploidies was proven what can be attributed to frequent meiosis errors, probably due to advanced maternal age (44 years at the first loss and 45 years at the second loss). In conclusion, aneuploidies can mimic partial hydatidiform mole. Genetic analysis is helpful on the one hand to rule out partial hydatidiform mole and on the other hand to identify aneuploidies and in this way to determine the cause of miscarriage.

• MeSH
• DNA MeSH
• dospělí MeSH
• lidé MeSH
• lidské chromozomy, pár 16 MeSH
• mola hydatidosa * diagnóza   genetika   MeSH
• mozaicismus MeSH
• nádory dělohy * diagnóza   genetika   MeSH
• samovolný potrat * diagnóza   genetika   MeSH
• těhotenství MeSH
• trizomie diagnóza   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• Názvy látek
• DNA MeSH

DNA methylation classifiers ("episignatures") help to determine the pathogenicity of variants of uncertain significance (VUS). However, their sensitivity is limited due to their training on unambiguous cases with strong-effect variants so that the classification of variants with reduced effect size or in mosaic state may fail. Moreover, episignature evaluation of mosaics as a function of their degree of mosaicism has not been developed so far. We improved episignatures with respect to three categories. Applying (i) minimum-redundancy-maximum-relevance feature selection we reduced their length by up to one order of magnitude without loss of accuracy. Performing (ii) repeated re-training of a support vector machine classifier by step-wise inclusion of cases in the training set that reached probability scores larger than 0.5, we increased the sensitivity of the episignature-classifiers by 30%. In the newly diagnosed patients we confirmed the association between DNA methylation aberration and age at onset of KMT2B-deficient dystonia. Moreover, we found evidence for allelic series, including KMT2B-variants with moderate effects and comparatively mild phenotypes such as late-onset focal dystonia. Retrained classifiers also can detect mosaics that previously remained below the 0.5-threshold, as we showed for KMT2D-associated Kabuki syndrome. Conversely, episignature-classifiers are able to revoke erroneous exome calls of mosaicism, as we demonstrated by (iii) comparing presumed mosaic cases with a distribution of artificial in silico-mosaics that represented all the possible variation in degree of mosaicism, variant read sampling and methylation analysis.

• MeSH
• alely MeSH
• fenotyp MeSH
• lidé MeSH
• metylace DNA * MeSH
• mnohočetné abnormality * genetika   MeSH
• mozaicismus MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

OBJECTIVE: Analysis of prenatal samples from 2015 to 2020. Comparison detection rates of clinically relevant variants by cytogenetic karyotype analysis and cytogenomic MLPA (Multiplex Ligation-Depent Probe Amplification) and microarray methods (CMA - chromosomal microarray). MATERIAL AND METHOD: 1,029 prenatal samples were analyzed by cytogenetic karyotyping (N = 1,029), cytogenomic methods - MLPA (N = 144) and CMA (N = 111). All unbalanced changes were confirmed by MLPA or CMA. RESULTS: From the analyzed set of fetuses, after subtraction of aneuploidies - 107 (10.40%, N = 1,029), 22 structural aberrations (2.39%, N = 922) - nine unbalanced changes (0.98%), 10 balanced changes (1.08%), one case of unclear mosaicism (0.09%), one case of presence of a marker chromosome (0.09%) and one case of sex discordance (0.09%) - were detected by karyotype analysis. A total of eight (7.21%, N = 111) pathological variants were detected by CMA in 255 samples with physiological karyotype indicated for cytogenomic examination. Five (3.47%, N = 144) of eight pathogenic variants were detected by MLPA method. The total capture of pathogenic variants by MLPA and CMA methods was 14 (5.14%) and 17 (6.25%) (N = 272), including confirmatory pathological karyotype testing. Detection of pathological variants in the isolated disorders group was lower than in the multiple disorders group (5.08 vs. 21.42%). CONCLUSION: A higher success rate for the detection of pathological copy number variation variants by the microarray method than by the MLPA method was confirmed.

• Klíčová slova
• CMA, MLPA, congenital developmental disorders, copy number variants,
• MeSH
• lidé MeSH
• mikročipová analýza MeSH
• mozaicismus MeSH
• multiplexová polymerázová řetězová reakce metody   MeSH
• plod MeSH
• prenatální diagnóza * metody   MeSH
• těhotenství MeSH
• variabilita počtu kopií segmentů DNA * MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Pathogenic variants affecting the BLM gene are responsible for the manifestation of extremely rare cancer‑predisposing Bloom syndrome. The present study reports on a case of an infant with a congenital hypotrophy, short stature and abnormal facial appearance. Initially she was examined using a routine molecular diagnostic algorithm, including the cytogenetic analysis of her karyotype, microarray analysis and methylation‑specific MLPA, however, she remained undiagnosed on a molecular level. Therefore, she and her parents were enrolled in the project of trio‑based exome sequencing (ES) using Human Core Exome kit. She was revealed as a carrier of an extremely rare combination of causative sequence variants altering the BLM gene (NM_000057.4), c.1642C>T and c.2207_2212delinsTAGATTC in the compound heterozygosity, resulting in a diagnosis of Bloom syndrome. Simultaneously, a mosaic loss of heterozygosity of chromosome 11p was detected and then confirmed as a borderline imprinting center 1 hypermethylation on chromosome 11p15. The diagnosis of Bloom syndrome and mosaic copy‑number neutral loss of heterozygosity of chromosome 11p increases a lifetime risk to develop any types of malignancy. This case demonstrates the trio‑based ES as a complex approach for the molecular diagnostics of rare pediatric diseases.

• Klíčová slova
• BLM gene, Bloom syndrome, cancer‑predisposing syndrome, copy‑number neutral loss of heterozygosity, exome sequencing,
• MeSH
• Bloomův syndrom * diagnóza   genetika   patologie   MeSH
• dítě MeSH
• heterozygot MeSH
• kojenec MeSH
• lidé MeSH
• lidský chromozom Y MeSH
• mozaicismus MeSH
• sekvenování exomu MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

BACKGROUND: Cardiac-urogenital syndrome [MIM # 618280] is a newly described very rare syndrome associated with pathogenic variants in the myelin regulatory factor (MYRF) gene that leads to loss of protein function. MYRF is a transcription factor previously associated only with the control of myelin-related gene expression. However, it is also highly expressed in other tissues and associated with various organ anomalies. The clinical picture is primarily dominated by complex congenital cardiac developmental defects, pulmonary hypoplasia, congenital diaphragmatic hernia, and urogenital malformations. CASE PRESENTATION: We present case reports of two siblings of unrelated parents in whom whole-exome sequencing was indicated due to familial occurrence of extensive developmental defects. A new, previously undescribed splicing pathogenic variant c.1388+2T>G in the MYRF gene has been identified in both patients. Both parents are unaffected, tested negative, and have another healthy daughter. The identical de novo event in siblings suggests gonadal mosaicism, which can mimic recessive inheritance. CONCLUSIONS: To our knowledge, this is the first published case of familial cardiac-urogenital syndrome indicating gonadal mosaicism.

• Klíčová slova
• MYRF gene, Scimitar syndrome, cardiac-urogenital syndrome, familiar occurrence, whole-exome sequencing,
• MeSH
• lidé MeSH
• mozaicismus * MeSH
• sekvenování exomu MeSH
• sourozenci * MeSH
• syndrom MeSH
• transkripční faktory genetika   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Myrf protein, human MeSH Prohlížeč
• transkripční faktory MeSH

BACKGROUND: In Turner syndrome (TS), fluorescent in situ hybridization (FISH) karyotyping offers an alternative to classical karyotyping. OBJECTIVE: We tested the added value of FISH karyotyping from lymphocytes (mesodermal origin), buccal cells (ectodermal origin), and a rear-tongue smear (endodermal origin) to determine the 45,X cell line fraction and its impact on patient phenotype. DESIGN AND PATIENTS: Classical karyotyping and three FISH assays were done in 153 girls and women previously diagnosed with TS in four university hospitals. The 45,X cell line fraction was determined for each method and correlated with the major phenotypic signs. RESULTS: Classical karyotyping identified 45,X/46,XX mosaicism in 77/153 subjects (50%), 45,X monosomy in 52/153 (34%), and other karyotypes in 24/153 (16%). FISH from lymphocytes verified 45,X in 47/52 original cases, whereas 4/52 had 45,X/46,XX and 1/52 45,X/47,XYY mosaicism. The 45,X cell line fraction was higher in FISH from lymphocytes compared to classical karyotyping (median 86.4% vs. 70.0%; p < 0.001), while there was no difference for FISH from buccal or rear-tongue smear cells. The mean 45,X cell line fraction was more abundant in patients with several of the characteristic phenotypic signs compared to patients without them (p < 0.01), but the predictive power was insufficient. CONCLUSION: FISH analysis confirmed the findings of classical karyotyping; only a few 45,X monosomy cases were reclassified as mosaics. The 45,X cell line fraction did not show clinically meaningful prediction of the phenotype. FISH analysis of buccal or rear-tongue epithelial cells may be a non-inferior, less invasive alternative to classical karyotyping.

• Klíčová slova
• Cytogenetics, Fluorescence in situ hybridization, Germ layers, Karyotype, Phenotype, Turner syndrome,
• MeSH
• epitelové buňky MeSH
• hybridizace in situ fluorescenční MeSH
• karyotypizace MeSH
• lidé MeSH
• lymfocyty metabolismus   MeSH
• monozomie MeSH
• mozaicismus MeSH
• Turnerův syndrom * metabolismus   MeSH
• ústní sliznice MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.

• MeSH
• chondrom * genetika   metabolismus   patologie   MeSH
• DNA nádorová * genetika   metabolismus   MeSH
• leiomyosarkom * genetika   metabolismus   patologie   MeSH
• lidé MeSH
• membránové proteiny * genetika   metabolismus   MeSH
• metylace DNA * MeSH
• mozaicismus * MeSH
• nádorové proteiny * genetika   metabolismus   MeSH
• nádory plic * genetika   metabolismus   patologie   MeSH
• nádory žaludku * genetika   metabolismus   patologie   MeSH
• nechromafinní paragangliom * genetika   metabolismus   patologie   MeSH
• promotorové oblasti (genetika) * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA nádorová * MeSH
• membránové proteiny * MeSH
• nádorové proteiny * MeSH
• SDHC protein, human MeSH Prohlížeč

Mutations occurring during embryonic development affect only a subset of cells resulting in two or more distinct cell populations that are present at different levels, also known as postzygotic mosaicism (PZM). Although PZM is a common biological phenomenon, it is often overlooked as a source of disease due to the challenges associated with its detection and characterization, especially for very low-frequency variants. Moreover, PZM can cause a different phenotype compared to constitutional mutations. Especially, lethal mutations in receptor tyrosine kinase (RTK) pathway genes, which exist only in a mosaic state, can have completely new clinical manifestations and can look very different from the associated monogenic disorder. However, some key questions are still not addressed, such as the level of mosaicism resulting in a pathogenic phenotype and how the clinical outcome changes with the development and age. Addressing these questions is not trivial as we require methods with the sensitivity to capture some of these variants hidden away in very few cells. Recent ultra-accurate deep-sequencing approaches can now identify these low-level mosaics and will be central to understand systemic and local effects of mosaicism in the RTK pathway. The main focus of this review is to highlight the importance of low-level mosaics and the need to include their detection in studies of genomic variation associated with disease.

• Klíčová slova
• gain of function, pathogenic variants, penetrance, postzygotic mosaicisms, tyrosine kinase receptor,
• MeSH
• dítě MeSH
• embryo savčí MeSH
• exprese genu MeSH
• fenotyp MeSH
• fibrózní dysplazie polyostotická enzymologie   genetika   patologie   MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   metabolismus   MeSH
• kojenec MeSH
• letální geny MeSH
• lidé MeSH
• mozaicismus * MeSH
• novorozenec MeSH
• Proteův syndrom enzymologie   genetika   patologie   MeSH
• signální transdukce MeSH
• Sturgeův-Weberův syndrom enzymologie   genetika   patologie   MeSH
• tyrosinkinasové receptory nedostatek   genetika   MeSH
• zárodečné mutace * MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• novorozenec MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• fosfatidylinositol-3-kinasy třídy I MeSH
• PIK3CA protein, human MeSH Prohlížeč
• tyrosinkinasové receptory MeSH

PURPOSE: To perform comprehensive genotyping of TSC1 and TSC2 in a cohort of 94 infants with tuberous sclerosis complex (TSC) and correlate with clinical manifestations. METHODS: Infants were enrolled at age <4 months, and subject to intensive clinical monitoring including electroencephalography (EEG), brain magnetic resonance imaging (MRI), and neuropsychological assessment. Targeted massively parallel sequencing (MPS), genome sequencing, and multiplex ligation-dependent probe amplification (MLPA) were used for variant detection in TSC1/TSC2. RESULTS: Pathogenic variants in TSC1 or TSC2 were identified in 93 of 94 (99%) subjects, with 23 in TSC1 and 70 in TSC2. Nine (10%) subjects had mosaicism. Eight of 24 clinical features assessed at age 2 years were significantly less frequent in those with TSC1 versus TSC2 variants including cortical tubers, hypomelanotic macules, facial angiofibroma, renal cysts, drug-resistant epilepsy, developmental delay, subependymal giant cell astrocytoma, and median seizure-free survival. Additionally, quantitative brain MRI analysis showed a marked difference in tuber and subependymal nodule/giant cell astrocytoma volume for TSC1 versus TSC2. CONCLUSION: TSC2 pathogenic variants are associated with a more severe clinical phenotype than mosaic TSC2 or TSC1 variants in TSC infants. Early assessment of gene variant status and mosaicism might have benefit for clinical management in infants and young children with TSC.

• Klíčová slova
• TSC1, TSC2, clinical manifestations, mosaicism, tuberous sclerosis complex (TSC),
• MeSH
• fenotyp MeSH
• hamartin genetika   MeSH
• kojenec MeSH
• lidé MeSH
• mozaicismus MeSH
• mutace MeSH
• předškolní dítě MeSH
• tuberin genetika   MeSH
• tuberózní skleróza * diagnostické zobrazování   genetika   MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• hamartin MeSH
• tuberin MeSH