• Klíčová slova
• Birk-Barel syndrom, Feingoldův syndrom typu 1,
• MeSH
• familiární hypofosfatemická rachitida diagnóza   genetika   MeSH
• kraniofaciální abnormality diagnóza   genetika   MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• nemoci kostí * diagnóza   genetika   MeSH
• sekvenování exomu * metody   MeSH
• svalová hypotonie diagnóza   genetika   MeSH
• synostóza diagnóza   genetika   MeSH
• vrozené deformity končetin diagnóza   genetika   MeSH
• Check Tag
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

PURPOSE: Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the "ClinVar low-hanging fruit" reanalysis, reasons for the failure of previous analyses, and lessons learned. METHODS: Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. RESULTS: We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). CONCLUSION: The "ClinVar low-hanging fruit" analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.

• MeSH
• alely MeSH
• genotyp MeSH
• lidé MeSH
• mentální retardace * diagnóza   genetika   MeSH
• sekvenování exomu MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Pathogenic sequence variant in the GNAI1 gene were recently introduced as a cause of novel syndrome with a manifestation of variable developmental delay and autistic features. In our study, we report a case of monozygotic twins with severe intellectual disability and motor delay and developmental dysphasia. Both probands and their parents were examined using multi-step molecular diagnostic algorithm including whole-exome sequencing (WES), resulting in the identification of a novel, de novo pathogenic sequence variant in the GNAI1 gene, NM_002069.6:c.815 A>G, p.(Asp272Gly) in probands. Using WES we also verified the microarray findings of a familial 8q24.23q24.3 duplication and heterozygous 5q13.2 deletion, not associated with clinical symptoms in probands. Our results confirmed the role of the GNAI1 gene in the pathogenesis of syndromic neurodevelopmental disorders. They support trio- or quatro-based WES as a suitable molecular diagnostics method for the simultaneous detection of clinically relevant sequence variants and CNVs in individuals with neurodevelopmental disorders and rare diseases.

• MeSH
• heterozygot MeSH
• lidé MeSH
• mentální retardace * diagnóza   genetika   MeSH
• neurovývojové poruchy * genetika   MeSH
• sekvenování exomu MeSH
• variabilita počtu kopií segmentů DNA MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

In this study we focus on the application of standardized tests aimed at evaluating the functional degree of independence in children (client 1, WeeFIM test; and client 2, FIM test) in special education diagnostics. The target group consisted of two clients with a diagnosis of mental functional diversity (n = 2; client 1: mild mental retardation, according to ICD-10: F70, aged 6.5 years; and client 2: moderate mental retardation, according to ICD-10: F71, aged 13.4 years). Special pedagogical intervention was primarily applied to the clients, focusing on identified deficits in the areas of cognitive, motor, and social skills. The presented results demonstrate the importance of the application of these tests in special pedagogy. An improvement in the observed indicators of the given tests was demonstrated for both probands after the intervention. The aim of this article was to draw attention to the suitability of using functional independence tests in special pedagogical practices. The authors discuss the further implications of this application for future practice.

• MeSH
• dítě MeSH
• lidé MeSH
• mentální retardace * diagnóza   MeSH
• speciální vzdělávání MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Syndrom intelektuálního postižení související s DYRK1A (DYRK1A-related intellectual disability syndrome) je autozomálně dominantní onemocnění charakterizované středním až těžkým intelektuálním postižením, zpožděním vývoje řeči, poruchou autistického spektra a mikrocefalií. Typické jsou kraniofaciální dysmorfie, potíže s krmením, malý vzrůst, hypertonie, poruchy chůze. V kojeneckém věku bývají často febrilní záchvaty, později vývoj epilepsie. Cílem našeho kazuistického sdělení je prezentace 3leté pacientky s tímto syndromem. U naší pacientky bylo vzhledem k vyčerpaným diagnostickým možnostem a neobjasněné příčině intelektuálního postižení provedeno celoexomové sekvenování (WES). Pomocí této metody jsme nalezli heterozygotní patogenní variantu p.R205* v genu DYRK1A, což umožnilo rychlé stanovení kauzální diagnózy. Lze tedy říct, že WES představuje účinný diagnostický nástroj pro detekci mutací, které jsou příčinou různých syndromů spojených s intelektuálním postižením.

DYRK1A-related intellectual disability syndrome is an autosomal dominant disorder characterized by intellectual disability including impaired speech development, autism spectrum disorder, and microcephaly. Affected individuals often have a clinically recognizable phenotype including typical craniofacial dysmorphism, feeding problems, hypertonia, short stature, gait disturbances, and foot anomalies. Other medical concerns relate to febrile seizures in infancy with later development of epilepsy. This case report aims to present a case of a three-year-old girl with DYRK1A syndrome. Since there were no additional diagnostic methods available and the cause of the intellectual disability remained unexplained, we decided to perform whole-exome sequencing (WES). WES led to the identification of heterozygous pathogenic variant p.R205* in DYRK1A gene and enabled us to reach a causal diagnosis in a reasonable time frame. We can conclude, that WES is an efficient diagnostic approach to identify causative genetic variants for syndromes associated with intellectual disability.

• Klíčová slova
• DYRK1A syndrom,
• MeSH
• diferenciální diagnóza MeSH
• komorbidita MeSH
• lidé MeSH
• mentální retardace * diagnóza   genetika   patologie   MeSH
• předškolní dítě MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   genetika   MeSH
• sekvenování exomu MeSH
• tyrosinkinasy antagonisté a inhibitory   genetika   MeSH
• Check Tag
• lidé MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

• MeSH
• diferenciální diagnóza MeSH
• dítě MeSH
• lidé MeSH
• mentální retardace * diagnóza   klasifikace   prevence a kontrola   MeSH
• pediatrie MeSH
• psychomotorické poruchy etiologie   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

KBG syndrome (KBGS) is characterized by distinctive facial gestalt, short stature and variable clinical findings. With ageing, some features become more recognizable, allowing a differential diagnosis. We aimed to better characterize natural history of KBGS. In the context of a European collaborative study, we collected the largest cohort of KBGS patients (49). A combined array- based Comparative Genomic Hybridization and next generation sequencing (NGS) approach investigated both genomic Copy Number Variants and SNVs. Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients. Epilepsy was present in 26.5%. Short stature was consistent over time, while occipitofrontal circumference (median value: -0.88 SD at birth) normalized over years. Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature reinforcing clinical suspicion in the paediatric age when short stature and vertebral/dental anomalies are vague. Macrodontia, oligodontia and dental agenesis (53%) were almost as frequent as skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age. In 28.5% of individuals, prenatal ultrasound anomalies were reported. Except for three splicing variants, leading to a premature termination, variants were almost all frameshift. Our results, broadening the spectrum of KBGS phenotype progression, provide useful tools to facilitate differential diagnosis and improve clinical management. We suggest to consider a wider range of dental anomalies before excluding diagnosis and to perform a careful odontoiatric/ear-nose-throat (ENT) evaluation in order to look for even submucosal palate cleft given the high percentage of palate abnormalities. NGS approaches, following evidence of antenatal ultrasound anomalies, should include ANKRD11.

• MeSH
• abnormality zubů * genetika   MeSH
• Evropané MeSH
• faciální stigmatizace MeSH
• fenotyp MeSH
• lidé MeSH
• mentální retardace * genetika   diagnóza   MeSH
• mnohočetné abnormality * genetika   diagnóza   MeSH
• nanismus * genetika   MeSH
• represorové proteiny genetika   MeSH
• srovnávací genomová hybridizace MeSH
• těhotenství MeSH
• vývojové onemocnění kostí * genetika   MeSH
• Check Tag
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

5,10-Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late-onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult-onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11-54). At onset (median age: 20 years; range 9-38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69-266, to 90 μmol/L, range 20-142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C-terminal regulatory domain of the protein were over-represented compared to early-onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%-58%). This series of patients with late-onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

• MeSH
• dítě MeSH
• dospělí MeSH
• epilepsie diagnóza   patologie   MeSH
• homocystinurie diagnóza   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mentální retardace diagnóza   patologie   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) nedostatek   MeSH
• mladiství MeSH
• mladý dospělý MeSH
• opožděná diagnóza MeSH
• psychotické poruchy diagnóza   patologie   MeSH
• retrospektivní studie MeSH
• svalová spasticita diagnóza   patologie   MeSH
• věk při počátku nemoci MeSH
• záchvaty diagnóza   patologie   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH

• MeSH
• dítě v pěstounské péči psychologie   MeSH
• dospělí MeSH
• inteligenční testy MeSH
• lidé MeSH
• mentální retardace * diagnóza   etiologie   komplikace   psychologie   MeSH
• methotrimeprazin aplikace a dávkování   terapeutické užití   MeSH
• porucha chování etiologie   farmakoterapie   MeSH
• psychologické techniky MeSH
• psychoterapie metody   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

BACKGROUND: Intellectual disability (ID) is a feature of many rare diseases caused by thousands of genes. This genetic heterogeneity implies that pathogenic variants in a specific gene are found only in a small number of patients, and difficulties arise in the definition of prevailing genotype and characteristic phenotype associated with that gene. One of such very rare disorders is autosomal recessive ID type 66 (OMIM #618221) caused by defects in C12orf4. Up to now, six families have been reported with mostly truncating variants. The spectrum of the clinical phenotype was not emphasized in previous reports, and detailed phenotype was not always available from previous patients, especially from large cohort studies. METHODS: Exome sequencing was performed in a consanguineous Armenian family with two affected adult brothers. RESULTS: The patients carry a novel homozygous nonsense C12orf4 variant. The integration of previous data and phenotyping of the brothers indicate that the clinical picture of C12orf4 defects involves hypotonia in infancy, rather severe ID, speech impairment, and behavioral problems such as aggressiveness, unstable mood, and autistic features. Several other symptoms are more variable and less consistent. CONCLUSION: This rather nonsyndromic and nonspecific clinical picture implies that additional patients with C12orf4 defects will likely continue to be identified using the "genotype-first" approach, rather than based on clinical assessment. The phenotype needs further delineation in future reports.

• MeSH
• alely MeSH
• dospělí MeSH
• faciální stigmatizace MeSH
• fenotyp * MeSH
• geny recesivní * MeSH
• homozygot MeSH
• intracelulární signální peptidy a proteiny genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• mentální retardace diagnóza   genetika   MeSH
• mutační analýza DNA MeSH
• pokrevní příbuzenství * MeSH
• předškolní dítě MeSH
• rodokmen MeSH
• sekvenování exomu MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Arménie MeSH