In the last decade, undiagnosed disease programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases. In our single-center study, we have launched a pilot program for pediatric patients with undiagnosed diseases in the second-largest university hospital in the Czech Republic. This study was prospectively conducted at the Department of Pediatrics at University Hospital Brno between 2020 and 2023. A total of 58 Czech patients with undiagnosed diseases were enrolled in the study. All children underwent singleton WES with targeted phenotype-driven analysis. We identified 28 variants, including 11 pathogenic, 13 likely pathogenic, and 4 VUS according to ACMG guidelines, as diagnostic of genetic diseases in 25 patients, resulting in an overall diagnostic yield of 43%. Eleven variants were novel and had not been previously reported in any public database. The overall clinical utility (actionability) enabling at least one type of change in the medical care of the patient was 76%, whereas the average number of clinical implications to individual patient care was two. Singleton WES facilitated the diagnostic process in the Czech undiagnosed pediatric population. We believe it is an effective approach to enable appropriate counseling, surveillance, and personalized clinical management.
- MeSH
- dítě MeSH
- genetické testování metody MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- nediagnostikované nemoci * genetika diagnóza epidemiologie MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- prospektivní studie MeSH
- sekvenování exomu * metody MeSH
- vzácné nemoci * genetika diagnóza MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- novorozenec MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika 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.
- 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
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
AIM: Extremely low birthweight (ELBW) neonates require a high protein intake, but this can be challenging in the very rare cases when they also have phenylketonuria (PKU). This is due to a lack of suitable parenteral nutrition or enteral formula. Our aim was to analyse tolerance to phenylalanine in these infants. MATERIAL: There are approximately 110 000 children born in the Czech Republic each year. A neonatal screening programme from 2005 to 2020 found that 320 neonates had PKU, including 30 premature neonates with a birth weight of less than 2500 g. RESULTS: This study focused on three neonates who were born with ELBWs of 720, 740 and 950 g, respectively. Phenylalanine levels normalised in ELBW neonates with PKU within 1 week of the introduction of low-phenylalanine parenteral or enteral nutrition. The tolerance to phenylalanine was very high (70-110 mg/kg) in the first months of life, due to a rapid weight gain, but significantly decreased during infancy. CONCLUSION: Extremely low birthweight neonates with PKU need special dietary management. Regular assessments of phenylalanine are necessary during the first weeks of life to allow prompt dietary adjustments that reflect rapid weight gain and transitory high tolerance to phenylalanine.
- MeSH
- fenylalanin MeSH
- fenylketonurie * diagnóza MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening MeSH
- parenterální výživa MeSH
- porodní hmotnost MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Alagille syndrome (ALGS) is a highly variable multisystem disorder inherited in an autosomal dominant pattern with incomplete penetration. The disorder is caused by mutations in the JAG1 gene, only rarely in the NOTCH2 gene, which gives rise to malformations in multiple organs. Bile duct paucity is the main characteristic feature of the disease. METHODS: Molecular-genetic examination of genes JAG1 and NOTCH2 in four probands of Czech origin who complied with the diagnostic criteria of ALGS was performed using targeted next-generation sequencing of genes JAG1 and NOTCH2. Segregation of variants in a family was assessed by Sanger sequencing of parental DNA. RESULTS: Mutations in the JAG1 gene were confirmed in all four probands. We identified two novel mutations: c.3189dupG and c.1913delG. Only in one case, the identified JAG1 mutation was de novo. None of the parents carrying JAG1 pathogenic mutation was diagnosed with ALGS. CONCLUSION: Diagnosis of the ALGS is complicated due to the absence of clear genotype-phenotype correlations and the extreme phenotypic variability in the patients even within the same family. This fact is of particular importance in connection to genetic counselling and prenatal genetic testing.
- Publikační typ
- časopisecké články MeSH
- MeSH
- dospělí MeSH
- genetické testování metody MeSH
- lidé MeSH
- mentální retardace genetika patologie MeSH
- neurovývojové poruchy * genetika MeSH
- novorozenec MeSH
- proteinfosfatasa 2C genetika MeSH
- výsledek terapie MeSH
- vývojové poruchy u dětí genetika patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Fenylketonurie (PKU) je autozomálně recesivně dědičná porucha metabolizmu aminokyseliny fenylalaninu, která je způsobena deficitem enzymu fenylalaninhydroxylázy v játrech. Neléčená PKU vede především k poruše kognitivních funkcí. Nejčastěji se k léčbě používá nízkobílkovinná dieta s nízkým obsahem fenylalaninu ve stravě (směsi aminokyselin bez fenylalaninu, glykomakropetid - GMP, neutrální aminokyseliny s dlouhým řetězcem - LNAAs). Snížené organoleptické vlastnosti nízkobílkovinné diety vedou ke špatné adherenci k dietě s možnou poruchou kognitivních a exekutivních funkcí. Z těchto důvodů se hledají nové možnosti léčby, tj. léčba pomocí kofaktoru BH4, enzymová náhradní terapie, využití probiotik a potenciálně i terapie genová. Evropská doporučení k diagnostice a léčbě PKU byla vytvořena s cílem optimalizovat léčbu PKU.
Phenylketonuria (PKU) is an autosomal recessive inherited disorder of the metabolism of the amino acid phenylalanine, which is caused by a deficiency of the enzyme phenylalanine hydroxylase in the liver. Untreated PKU primarily leads to cognitive impairment. The most commonly used treatment is a low-protein diet with a low content of phenylalanine in the diet (phenylalanine free amino acid mixtures, glycomacropeptide-GMP, neutral long-chain amino acids-LNNAs). Decreased organoleptic properties of a low-protein diet lead to poor adherence to a diet with possible cognitive and executive dysfunction. For this reasons, new treatment options are sought, ei. treatment with cofactor BH4, enzyme replacement therapy, the use of probiotics and potentially gene therapy. The Key European Guidelines for the diagnosis and manamegent of patients with phenylketonuria (PKU) were developed to optimise PKU care.
- MeSH
- enzymová substituční terapie metody MeSH
- fenylalanin krev MeSH
- fenylalaninhydroxylasa genetika MeSH
- fenylketonurie * dietoterapie farmakoterapie genetika MeSH
- genetická terapie metody MeSH
- kognitivní poruchy etiologie metabolismus patofyziologie MeSH
- lidé MeSH
- nízkoproteinová dieta * metody MeSH
- probiotika terapeutické užití MeSH
- směrnice pro lékařskou praxi jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
