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Kabuki Syndrome (KS) encompasses a spectrum of clinical manifestations, primarily attributed to pathogenic variants in the KMT2D gene. This study aims to elucidate novel features in KS patients with missense variants, contrasting their presentation with both literature-reported cases of patients with missense pathogenic variants as well as other KS patients with truncating pathogenic variants. Employing a survey questionnaire and clinical evaluations, we examined ten KS patients with missense variants, focusing on their dysmorphism characteristics, behavior and psychomotor development. We identified unique features in missense variant patients, including foot hyperesthesia, musicality, and sensory integration disorders. Notably, despite similarities in developmental trajectories, distinct phenotypic traits emerged in missense variant cases, suggesting a potential genotype-phenotype correlation. These findings contribute to a deeper understanding of KS heterogeneity and underscore the importance of genotype-specific characterization for prognostic and therapeutic considerations. Further exploration of genotype-phenotype relationships promises to refine clinical management strategies and enhance patient outcomes in this complex syndrome.
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Hyponatraemia, defined as sodium concentration below 135 mmol/l, is one of the most common electrolyte imbalances. Differential diagnosis of hyponatraemia is difficult. We describe 3 cases of children with transient, severe hyponatraemia (< 125 mmol/l). While diagnosing hyponatraemia, it is of major importance to carefully ask in the anamnesis about habits related to the amount of fluid intake and the type of consumed fluids. It should also be noted that a frequent procedure during an infection is to increase fluid ingesting as a prevention of dehydration. One, however, should remember about the possibility of inducing water poisoning in a patient consuming excessive amounts of hypotonic fluids, especially when exposed to non-osmotic antidiuretic hormone stimulus, such as an acute infection or stress, and/or reduced renal excretory capacity. Only the presence of polyuria does not justify a diagnosis of arginine vasopressin deficiency (AVP-D), and especially the implementation of desmopressin treatment before all diagnostic procedures are completed, specifically in the case of hyponatraemia. Desmopressin can be used simultaneously with intravenous 3% saline solution only in the treatment of a very severe hyponatraemia, to avoid overcorrection of natraemia. In patients after profound hyponatraemia, polyuria can be observed after normalisation of fluid intake, but it is temporary.
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Hiponatremia , Humanos , Hiponatremia/etiología , Hiponatremia/diagnóstico , Masculino , Femenino , Niño , Preescolar , Lactante , Desamino Arginina Vasopresina/uso terapéuticoRESUMEN
Background: Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder affecting psychomotor, social, and intellectual development, caused by a mutation in the TCF4 gene. The study aims to gather the phenotype and genotype data of PTHS patients from Poland and to assess the quality of life (QoL) and the impact of the disorders on the family. Methods: Eight families with PTHS participated in the study. To obtain data, the following standardized questionnaires were used: Questionnaire on Clinical Problems (QCP), the PedsQL™ Family Impact Module, and the QL-Disability Questionnaire. Additionally, a retrospective analysis of clinical examination, genetic consult, medical history, and genotype of each individual was performed. Results: All of the examined children exhibited a mutation in the TCF4 gene and typical features of PTHS. The most prevalent clinical symptoms in the study group included typical PTHS appearance, intellectual disability (n = 5; as the rest of the patients were too young to be assessed), abnormal speech development (n = 8), reduced pain response (n = 7), constipation (n = 7), drooling (n = 7), cold extremities (n = 7), and disturbances in sensory integration processes (n = 7). The QL-Disability Questionnaire revealed a total QoL score of 67.7/100 for children with PTHS, while the QoL for their families in the PedsQL Family Impact Module was 53.82/100. The highest-rated domain was cognitive functioning (Median (Me) = 67.50; Standard Deviation (SD) = 21.95), while the lowest was daily activities (Me = 25.00; SD = 29.86). Conclusions: The study allowed the collection of data on the phenotype and genotype of children with PTHS living in Poland. Overall, our study showed that the QoL of children with PTHS is impaired.
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Intellectual disability with speech delay and behavioural abnormalities, as well as hypotonia, seizures, feeding difficulties and craniofacial dysmorphism, are the main symptoms associated with pathogenic variants of the ZMYND11 gene. The range of clinical manifestations of the ZMYND phenotype is constantly being expanded by new cases described in the literature. Here, we present two previously unreported paediatric patients with neurodevelopmental challenges, who were diagnosed with missense variants in the ZMYND11 gene. It should be noted that one of the individuals manifested with hyperinsulinaemic hypoglycaemia (HH), a symptom that was not described before in published works. The reason for the occurrence of HH in our proband is not clear, so we try to explain the origin of this symptom in the context of the ZMYND11 syndrome. Thus, this paper contributes to knowledge on the range of possible manifestations of the ZMYND disease and provides further evidence supporting its association with neurodevelopmental challenges.
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Anomalías Múltiples , Discapacidad Intelectual , Niño , Humanos , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Proteínas de Ciclo Celular/genética , Proteínas Co-Represoras/genética , Proteínas de Unión al ADN/genética , Discapacidad Intelectual/genética , Discapacidad Intelectual/diagnóstico , Mutación Missense , Fenotipo , SíndromeRESUMEN
SMC1A epilepsy syndrome or developmental and epileptic encephalopathy-85 with or without midline brain defects (DEE85, OMIM #301044) is an X-linked neurologic disorder associated with mutations of the SMC1A gene, which is also responsible for about 5% of patients affected by Cornelia de Lange syndrome spectrum (CdLS). Only described in female patients, SMC1A epilepsy syndrome is characterized by the onset of severe refractory epileptic seizures in the first year of life, global developmental delay, a variable degree of intellectual disability, and dysmorphic facial features not typical of CdLS. This was a descriptive observational study for the largest international cohort with this specific disorder. The main goal of this study was to improve the knowledge of the natural history of this phenotype with particular attention to the psychomotor development and the epilepsy data. The analyzed cohort shows normal prenatal growth with the subsequent development of postnatal microcephaly. The incidence of neonatal problems (seizures and respiratory compromise) is considerable (51.4%). There is a significant prevalence of central nervous system (20%) and cardiovascular malformations (20%). Motor skills are generally delayed. The presence of drug-resistant epilepsy is confirmed; the therapeutic role of a ketogenic diet is still uncertain. The significant regression of previously acquired skills following the onset of seizures has been observed. Facial dysmorphisms are variable and no patient shows a classic CdLS phenotype. To sum up, SMC1A variants caused drug-resistant epilepsy in these patients, more than two-thirds of whom were shown to progress to developmental and epileptic encephalopathy. The SMC1A gene variants are all different from each other (apart from a couple of monozygotic twins), demonstrating the absence of a mutational hotspot in the SMC1A gene. Owing to the absence of phenotypic specificity, whole-exome sequencing is currently the diagnostic gold standard.
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Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Mutación , Humanos , Femenino , Masculino , Proteínas de Ciclo Celular/genética , Proteínas Cromosómicas no Histona/genética , Preescolar , Lactante , Mutación/genética , Niño , Epilepsia/genética , Epilepsia/epidemiología , Epilepsia/patología , Epilepsia/diagnóstico , Fenotipo , Estudios de Cohortes , Adolescente , Recién Nacido , Síndromes Epilépticos/genética , Síndromes Epilépticos/epidemiología , Síndrome de Cornelia de Lange/genética , Síndrome de Cornelia de Lange/epidemiología , Síndrome de Cornelia de Lange/patologíaRESUMEN
Congenital alveolar dysplasia (CAD) belongs to rare lethal lung developmental disorders (LLDDs) in neonates, manifesting with acute respiratory failure and pulmonary arterial hypertension refractory to treatment. The majority of CAD cases have been associated with copy-number variant (CNV) deletions at 17q23.1q23.2 or 5p12. Most CNV deletions at 17q23.1q23.2 were recurrent and encompassed two closely located genes, TBX4 and TBX2. In a few CAD cases, intragenic frameshifting deletions or single-nucleotide variants (SNVs) involved TBX4 but not TBX2. Here, we describe a male neonate who died at 27 days of life from acute respiratory failure caused by lung growth arrest along the spectrum of CAD confirmed by histopathological assessment. Trio-based genome sequencing revealed in the proband a novel non-recurrent ~1.07 Mb heterozygous CNV deletion at 17q23.2, encompassing TBX4 that arose de novo on the paternal chromosome. This is the first report of a larger-sized CNV deletion in a CAD patient involving TBX4 and leaving TBX2 intact. Our results, together with previous reports, indicate that perturbations of TBX4, rather than TBX2, cause severe lung phenotypes in humans.
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Síndrome de Dificultad Respiratoria del Recién Nacido , Insuficiencia Respiratoria , Humanos , Recién Nacido , Masculino , Hipertensión Pulmonar Primaria Familiar , Pulmón , Fenotipo , Proteínas de Dominio T Box/genéticaRESUMEN
Esophageal atresia (EA) is the most common malformation of the upper gastrointestinal tract. The estimated incidence of EA is 1 in 3500 births. EA is more frequently observed in boys and in twins. The exact cause of isolated EA remains unknown; a multifactorial etiology, including epigenetic gene expression modifications, is considered. The study included six pairs of twins (three pairs of monozygotic twins and three pairs of dizygotic twins) in which one child was born with EA as an isolated defect, while the other twin was healthy. DNA samples were obtained from the blood and esophageal tissue of the child with EA as well as from the blood of the healthy twin. The reduced representation bisulfite sequencing (RRBS) technique was employed for a whole-genome methylation analysis. The analyses focused on comparing the CpG island methylation profiles between patients with EA and their healthy siblings. Hypermethylation in the promoters of 219 genes and hypomethylation in the promoters of 78 genes were observed. A pathway enrichment analysis revealed the statistically significant differences in methylation profile of 10 hypermethylated genes in the Rho GTPase pathway, previously undescribed in the field of EA (ARHGAP36, ARHGAP4, ARHGAP6, ARHGEF6, ARHGEF9, FGD1, GDI1, MCF2, OCRL, and STARD8).
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Atresia Esofágica , Masculino , Niño , Humanos , Atresia Esofágica/genética , Gemelos Monocigóticos/genética , Gemelos Dicigóticos , Islas de CpG/genética , Epigénesis Genética , Proteínas Proto-Oncogénicas , Factores de Intercambio de Guanina Nucleótido , Factores de Intercambio de Guanina Nucleótido RhoRESUMEN
BACKGROUND: Say-Barber-Biesecker-Young-Simpson (SBBYSS) variant of Ohdo syndrome is a rare, autosomal dominant and clinically heterogenous disorder, caused by pathogenic variants in the KAT6B gene located on chromosome 10q22.2. KAT6B encodes a highly conserved histone acetyltransferase belonging to the MYST family. Currently, diseases caused by pathogenic variants in KAT6B (KAT6B-related disorders) comprise two allelic entities: SBBYSS variant of Ohdo syndrome and genitopatellar syndrome (GPS). Increase in the number of cases with overlapping GPS/SBBYSS phenotype which makes it necessary to redefine this group of phenotypes as KAT6B-related disorders or KAT6B spectrum disorders. Individuals with SBBYSS usually present with facial abnormalities, hypotonia, joint laxity, feeding problems, and long thumbs/great toes. This syndrome also typically involves skeletal problems including patellar hypoplasia/agenesis. METHODS: Here we report six SBBYS syndrome patients with the same dysmorphic features but a different course of the disease. One known and five novel KATB6 pathogenic variants were identified by molecular diagnostics using Next Generation Sequencing (NGS). RESULTS: We present a detailed phenotypic analysis of six individuals with KAT6B-related disorders, in whom a heterozygous pathogenic variant in KAT6B gene was found. In all of our patients facial dysmorphism as well as developmental and speech delay were present. Additionally, all but one patients presented with hypotonia, ocular abnormalities and long thumbs. Most of our probands showed blepharophimosis and skeletal (mainly knee) defects. Contrary to previously reported severe patellar defects (hypoplasia/agenesis) anomalies presented by our patients were less severe (dysplasia, habitual dislocation, subluxation) referring to KAT6B-related disorders. CONCLUSION: While most of the anomalies found in our patients comply with SBBYSS criteria, phenotypic differences in our probands support a broader spectrum of the disease phenotype. To establish the range of this spectrum, a detailed analysis of clinical variability among patients with SBBYSS requires further investigation.
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Discapacidad Intelectual , Hipotonía Muscular , Masculino , Humanos , Mutación , Hipotonía Muscular/genética , Polonia , Discapacidad Intelectual/genética , Histona Acetiltransferasas/genéticaRESUMEN
BACKGROUND: KIF1A (kinesin family member 1A)-related disorders encompass a variety of diseases. KIF1A variants are responsible for autosomal recessive and dominant spastic paraplegia 30 (SPG, OMIM610357), autosomal recessive hereditary sensory and autonomic neuropathy type 2 (HSN2C, OMIM614213), and autosomal dominant neurodegeneration and spasticity with or without cerebellar atrophy or cortical visual impairment (NESCAV syndrome), formerly named mental retardation type 9 (MRD9) (OMIM614255). KIF1A variants have also been occasionally linked with progressive encephalopathy with brain atrophy, progressive neurodegeneration, PEHO-like syndrome (progressive encephalopathy with edema, hypsarrhythmia, optic atrophy), and Rett-like syndrome. MATERIALS AND METHODS: The first Polish patients with confirmed heterozygous pathogenic and potentially pathogenic KIF1A variants were analyzed. All the patients were of Caucasian origin. Five patients were females, and four were males (female-to-male ratio = 1.25). The age of onset of the disease ranged from 6 weeks to 2 years. RESULTS: Exome sequencing identified three novel variants. Variant c.442G>A was described in the ClinVar database as likely pathogenic. The other two novel variants, c.609G>C; p.(Arg203Ser) and c.218T>G, p.(Val73Gly), were not recorded in ClinVar. CONCLUSIONS: The authors underlined the difficulties in classifying particular syndromes due to non-specific and overlapping signs and symptoms, sometimes observed only temporarily.
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Enfermedades Neurodegenerativas , Espasmos Infantiles , Paraplejía Espástica Hereditaria , Humanos , Masculino , Femenino , Lactante , Polonia , Cinesinas/genética , Paraplejía Espástica Hereditaria/patología , AtrofiaRESUMEN
Fetal alcohol spectrum disorder (FASD) encompasses neurodevelopmental disabilities and physical birth defects associated with prenatal alcohol exposure. Previously, we attempted to identify epigenetic biomarkers for FASD by investigating the genome-wide DNA methylation (DNAm) profiles of individuals with FASD compared to healthy controls. In this study, we generated additional gene expression profiles in a subset of our previous FASD cohort, encompassing the most severely affected individuals, to examine the functional integrative effects of altered DNAm status on gene expression. We identified six differentially methylated regions (annotated to the SEC61G, REEP3, ZNF577, HNRNPF, MSC, and SDHAF1 genes) associated with changes in gene expression (p-value < 0.05). To the best of our knowledge, this study is the first to assess whole blood gene expression and DNAm-gene expression associations in FASD. Our results present novel insights into the molecular footprint of FASD in whole blood and opens opportunities for future research into multi-omics biomarkers for the diagnosis of FASD.
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Trastornos del Espectro Alcohólico Fetal , Efectos Tardíos de la Exposición Prenatal , Humanos , Femenino , Embarazo , Trastornos del Espectro Alcohólico Fetal/diagnóstico , Trastornos del Espectro Alcohólico Fetal/genética , Efectos Tardíos de la Exposición Prenatal/genética , Fenotipo , Metilación de ADN , Biomarcadores , Canales de Translocación SEC/genéticaRESUMEN
BACKGROUND: Menkes disease (MD; OMIM #309400) is a progressive neurodegeneration that results from abnormalities in the copper metabolism which are already present before birth. It is an extremely rare condition. The study was conducted to assess the quality of life of children with MD syndrome and the impact of the disease on family functioning. METHODS: A cross-sectional questionnaire survey was used. The subjects were 16 parents of children with MD. The method used was the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module and the author's own questionnaire. RESULTS: Quality of life (QOL) was 29.14 (SD = 14.73), with the lowest for physical functioning (M = 10.55; SD = 10.26) and highest for emotional functioning (M = 48.13; SD = 29.43). The highest score was on the family relationships domain (M = 56.25, SD = 20.38) and the cognitive functioning domain (M = 50.00, SD = 19.24) and the lowest was on the daily activities' domain (M = 32.29, SD = 20.38) and the physical functioning domain (M = 39.84, SD = 14.90). The analysis did not show statistically significant relationships between age (p = 0.193) and the number of epileptic seizures a week (p = 0.641) and the overall QOL of the children studied. No statistically significant relationships were found between treatment with copper histidine and the overall QOL of the children (p = 0.914) and in physical functioning (p = 0.927), emotional functioning (p = 0.706), and social functioning (p = 0.751). The presence of comorbidities did not have an influence on the overall QOL. CONCLUSIONS: MD has a moderate impact on the functioning of the families of the affected children. The age of the child, number of epileptic seizures a week, feeding method (oral feeding or feeding via a PEG tube), and treatment with copper histidine do not have a significant impact on the QOL of children with MD.
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Neural differentiation, synaptic transmission, and action potential propagation depend on membrane sphingolipids, whose metabolism is tightly regulated. Mutations in the ceramide transporter CERT (CERT1), which is involved in sphingolipid biosynthesis, are associated with intellectual disability, but the pathogenic mechanism remains obscure. Here, we characterize 31 individuals with de novo missense variants in CERT1. Several variants fall into a previously uncharacterized dimeric helical domain that enables CERT homeostatic inactivation, without which sphingolipid production goes unchecked. The clinical severity reflects the degree to which CERT autoregulation is disrupted, and inhibiting CERT pharmacologically corrects morphological and motor abnormalities in a Drosophila model of the disease, which we call ceramide transporter (CerTra) syndrome. These findings uncover a central role for CERT autoregulation in the control of sphingolipid biosynthetic flux, provide unexpected insight into the structural organization of CERT, and suggest a possible therapeutic approach for patients with CerTra syndrome.
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Ceramidas , Esfingolípidos , Humanos , Ceramidas/metabolismo , Homeostasis , Mutación , Esfingolípidos/genética , Esfingolípidos/metabolismoRESUMEN
PURPOSE: Biallelic PIGN variants have been described in Fryns syndrome, multiple congenital anomalies-hypotonia-seizure syndrome (MCAHS), and neurologic phenotypes. The full spectrum of clinical manifestations in relation to the genotypes is yet to be reported. METHODS: Genotype and phenotype data were collated and analyzed for 61 biallelic PIGN cases: 21 new and 40 previously published cases. Functional analysis was performed for 2 recurrent variants (c.2679C>G p.Ser893Arg and c.932T>G p.Leu311Trp). RESULTS: Biallelic-truncating variants were detected in 16 patients-10 with Fryns syndrome, 1 with MCAHS1, 2 with Fryns syndrome/MCAHS1, and 3 with neurologic phenotype. There was an increased risk of prenatal or neonatal death within this group (6 deaths were in utero or within 2 months of life; 6 pregnancies were terminated). Incidence of polyhydramnios, congenital anomalies (eg, diaphragmatic hernia), and dysmorphism was significantly increased. Biallelic missense or mixed genotype were reported in the remaining 45 cases-32 showed a neurologic phenotype and 12 had MCAHS1. No cases of diaphragmatic hernia or abdominal wall defects were seen in this group except patient 1 in which we found the missense variant p.Ser893Arg to result in functionally null alleles, suggesting the possibility of an undescribed functionally important region in the final exon. For all genotypes, there was complete penetrance for developmental delay and near-complete penetrance for seizures and hypotonia in patients surviving the neonatal period. CONCLUSION: We have expanded the described spectrum of phenotypes and natural history associated with biallelic PIGN variants. Our study shows that biallelic-truncating variants usually result in the more severe Fryns syndrome phenotype, but neurologic problems, such as developmental delay, seizures, and hypotonia, present across all genotypes. Functional analysis should be considered when the genotypes do not correlate with the predicted phenotype because there may be other functionally important regions in PIGN that are yet to be discovered.
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Anomalías Múltiples , Trastornos Congénitos de Glicosilación , Epilepsia , Hernia Diafragmática , Embarazo , Femenino , Humanos , Hipotonía Muscular/genética , Epilepsia/genética , Anomalías Múltiples/genética , Hernia Diafragmática/genética , Convulsiones/genética , Fenotipo , Estudios de Asociación Genética , SíndromeRESUMEN
Background: Down Syndrome (DS; OMIM #190685), known as trisomy 21, is one of the most common genetic disorders in the human population and the commonest known cause of intellectual disability. The study was conducted to investigate the quality of life (QoL) of children with DS syndrome and its impact on family functioning. Purpose of study: To assess the quality of life of children with trisomy 21 and the impact of the disorder on the family. Methods: We used a cross-sectional questionnaire study. The respondents were 52 parents of children with trisomy 21. The following structured questionnaires were used: the PedsQL™ 4.0 Generic Core Scales, the PedsQL™ Family Impact Module and Study-Specific Questionnaire (SSQ). Results: The combined scores, with a mean value of approximately 55 out of a possible 100 points, indicated a significant impact of the child's genetic defect on family functioning. In the overall QOL, the highest rated domain was physical functioning (xÌ =60.14; SD = 23.82) and the lowest was school functioning (xÌ =51.36; SD = 18.72). Better school functioning (p = 0.022) was reported for girls. The presence of reduced muscle tone also had a negative impact on the child's functioning in the physical (p = 0.036), emotional (p = 0.011), psychosocial (p = 0.027) and overall QOL domains (p = 0.023). Conclusion: Overall, our results showed that the quality of life of children with trisomy 21 is impaired. There was a positive association between the child's QOL and the QOL of their parents, as well as the general functioning of the child's whole family. For this reason, an improvement in the QOL of parents and the family functioning is closely related to an increased QOL of the child. The continuous deepening of knowledge of QOL in individual trisomy 21 management allows for better preparation and ongoing care for the patients concerned.
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Objective: Prader−Willi (PWS; OMIM#176270) syndrome is a clinically distinct genetic disorder, caused by an abnormality in the 15q11-q13 region, referred to as the critical region. One of the most popular concepts existing in modern sciences, not only within psychology, but also in the aspect of all sciences that are related to human life and its course, is the quality of life (QoL). Though it is known that health-related quality of life in children with PWS can be reduced, less is understood about the impact on the family. We aimed to identify factors related to the quality of life of children with PWS and the impact of the disease on family functioning. Methods: A cross-sectional questionnaire survey. The subjects were 46 parents of children with PWS. The Computer Assisted Self-Interviewing (CASI) method was used; the Paediatric Quality of Life Inventory and the PedsQL Family Impact Module. Results: The PedsQL mean score was 49.0; (min−max: 5.6−90.8; SD = 16.8), with the highest scores in the Emotional Functioning (EF) (EF; 55.9; min−max: 5.0−100.0; SD = 22.0), and the lowest in the Social Functioning (SF) (SF; 42.7; min−max: 5.0−85.0; SD = 18.7) 56.4 (SD ± 14.7). The child's age does not affect the quality of life, there were no statistically significant (p > 0.05). families have difficulties in performing daily activities (total score 27.6; SD 16.7), support family functioning (total score 28.9; SD 18.8) and effects physical domain (total score 27.7; SD 15.7). Conclusion: Research on the QoL of patients with PWS and their families is very important in order to assess the QoL, but also to provide the perspective of an active change in the perspective of a better treatment process, rehabilitation and communication in society.
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Síndrome de Prader-Willi , Niño , Humanos , Calidad de Vida/psicología , Estudios Transversales , Encuestas y Cuestionarios , Ajuste SocialRESUMEN
COQ8A-ataxia is a mitochondrial disease in which a defect in coenzyme Q10 synthesis leads to dysfunction of the respiratory chain. The disease is usually present as childhood-onset progressive ataxia with developmental regression and cerebellar atrophy. However, due to variable phenotype, it may be hard to distinguish from other mitochondrial diseases and a wide spectrum of childhood-onset cerebellar ataxia. COQ8A-ataxia is a potentially treatable condition with the supplementation of coenzyme Q10 as a main therapy; however, even 50% may not respond to the treatment. In this study we review the clinical manifestation and management of COQ8A-ataxia, focusing on current knowledge of coenzyme Q10 supplementation and approach to further therapies. Moreover, the case of a 22-month-old girl with cerebellar ataxia and developmental regression will be presented.
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Pseudouridine (Ψ) is an RNA base modification ubiquitously found in many types of RNAs. In humans, the isomerization of uridine is catalyzed by different stand-alone pseudouridine synthases (PUS). Genomic mutations in the human pseudouridine synthase 3 gene (PUS3) have been identified in patients with neurodevelopmental disorders. However, the underlying molecular mechanisms that cause the disease phenotypes remain elusive. Here, we utilize exome sequencing to identify genomic variants that lead to a homozygous amino acid substitution (p.[(Tyr71Cys)];[(Tyr71Cys)]) in human PUS3 of two affected individuals and a compound heterozygous substitution (p.[(Tyr71Cys)];[(Ile299Thr)]) in a third patient. We obtain wild-type and mutated full-length human recombinant PUS3 proteins and characterize the enzymatic activity in vitro. Unexpectedly, we find that the p.Tyr71Cys substitution neither affect tRNA binding nor pseudouridylation activity in vitro, but strongly impair the thermostability profile of PUS3, while the p.Ile299Thr mutation causes protein aggregation. Concomitantly, we observe that the PUS3 protein levels as well as the level of PUS3-dependent Ψ levels are strongly reduced in fibroblasts derived from all three patients. In summary, our results directly illustrate the link between the identified PUS3 variants and reduced Ψ levels in the patient cells, providing a molecular explanation for the observed clinical phenotypes.
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Hidroliasas , Discapacidad Intelectual , Seudouridina , Humanos , Hidroliasas/genética , Hidroliasas/metabolismo , Discapacidad Intelectual/genética , Seudouridina/genética , Seudouridina/metabolismo , Procesamiento Postranscripcional del ARNRESUMEN
Skeletal dysplasias (SDs) are a large, heterogeneous group of mostly genetic disorders that affect the bones and cartilage, resulting in abnormal growth and development of skeletal structures. The high clinical and genetic diversity in SDs cause difficulties in prenatal diagnosis. To establish a correct prognosis and better management, it is very important to distinguish SDs with poor life-limiting prognosis or lethal SDs from other ones. Bad prognosis in foetuses is assessed on the basis of the size of the thorax, lung volumes, long bones' length, bones' echogenicity, bones' angulation or presented fractures, and the concomitant presence of non-immune hydrops or visceral abnormalities. To confirm SD diagnosis and perform family genetic consultation, rapid molecular diagnostics are needed; therefore, the NGS method using a panel of genes corresponding to SD or whole-exome sequencing (WES) is commonly used. We report a case of a foetus showing long bones' shortening and a narrow chest with short ribs, diagnosed prenatally with asphyxiating thoracic dystrophy, also known as Jeune syndrome (ATD; OMIM 208500), caused by compound heterozygous variants in the DYNC2H1 gene, identified by prenatally performed rapid-WES analysis. The missense variants in the DYNC2H1 gene were inherited from the mother (c.7289T>C; p.Ile2430Thr) and from the father (c.12716T>G; p.Leu4239Arg). The DYNC2H1 gene is one of at least 17 ATD-associated genes. This disorder belongs to the ninth group of SD, ciliopathies with major skeletal involvement. An extremely narrow, bell-shaped chest, and abnormalities of the kidneys, liver, and retinas were observed in most cases of ATD. Next to lethal and severe forms, clinically mild forms have also been reported. A diagnosis of ATD is important to establish the prognosis and management for the patient, as well as the recurrence risk for the family.
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Dineínas Citoplasmáticas , Diagnóstico Prenatal , Dineínas Citoplasmáticas/genética , Diagnóstico Diferencial , Síndrome de Ellis-Van Creveld , Femenino , Humanos , Mutación , Embarazo , Secuenciación del ExomaRESUMEN
Aim: This study reports the reliability and validity of the Polish version of the Esophageal Atresia Quality of Life (EA-QOL) questionnaires, which were originally developed in Sweden and Germany. Methods: A total of 50 families of children (23 aged 2 to 7, and 27 aged 8 to 17) with EA/TEF (esophageal atresia/tracheoesophageal fistula) participated in the study. The development and validation of the Polish version of the EA-QOL involved forward-backward translation of the survey items following the guidelines for cross-cultural translation, cognitive debriefing and evaluation of psychometric properties, including assessment of internal and retest reliability, linguistic validity, content validity, known-group validity and convergent validity. The medical records of patients and standardized questionnaires were used to obtain clinical data. The level of significance was p < 0.05. Results: The Polish versions of the EA-QOL questionnaires demonstrated strong linguistic and content validity, are slightly discriminative for esophageal and respiratory problems, but do not show convergent validity with the PedsQL 4.0 generic core scales. In terms of reliability, the internal consistency of the subscale and total scale of Polish versions as measured by Cronbach's alpha is good, and retest reliability is excellent. Conclusions: The Polish versions of the EA-QOL questionnaires meet most psychometric criteria that confirm the EA-QOL questionnaires' reliability and validity. This study enables application of these questionnaires in future research among children with EA in Poland and participation in international multicenter studies focusing on advancing knowledge of condition-specific QOL in this population. Future cross-cultural research using larger sample sizes is still needed to better address the relationship between condition-specific and generic QOL, as well as the discriminative ability of the EA-QOL questionnaires.
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Atresia Esofágica , Calidad de Vida , Adolescente , Niño , Humanos , Polonia , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Fístula TraqueoesofágicaRESUMEN
Surfactant is a complex of phospholipids and proteins produced in type II pneumocytes. Its deficiency frequently occurs in preterm infants and causes respiratory distress syndrome. In full-term newborns, its absence results from mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes involved in the surfactant metabolism. ABCA3 encodes ATP-binding cassette, which is responsible for transporting phospholipids in type II pneumocytes. We present a case of a male late preterm newborn with inherited surfactant deficiency in whom we identified the likely pathogenic c.604G>A variant in one allele and splice region/intron variant c.4036-3C>G of uncertain significance in the second allele of ABCA3. These variants were observed in trans configuration. We discuss the diagnostic challenges and the management options. Although invasive treatment was introduced, only temporary improvement was observed. We want to raise awareness about congenital surfactant deficiency as a rare cause of respiratory failure in term newborns.