Presence Of Dysmorphic Features Research Articles

Validation of targeted next-generation sequencing panels in a cohort of Polish patients with epilepsy: assessing variable performance across clinical endophenotypes and uncovering novel genetic variants.

Targeted Next-Generation Sequencing Panels (TNGSP) have become a standard in global clinical practice. Instead of questioning the necessity of next-generation sequencing in epilepsy patients, contemporary large-scale research focuses on factors such as the size of TNGSP, the comparative advantages of exome or genome-wide sequencing over TNGSP, and the impact of clinical, electrophysiological, and demographic variables on genetic test performance. This study aims to elucidate the demographic and clinical factors influencing the performance of TNGSP in 138 Polish patients with epilepsy, recognizing the pivotal role of genetic testing in guiding patient management and therapy. A retrospective analysis was conducted on patients from a genetic clinic in Poznań, Poland, who underwent commercial gene panel studies at Invitae Corporation (USA) between 2020 and 2022. Patient groups were defined based on the age of onset of the first epileptic seizures, seizure type, gender, fever dependence of seizures, presence of intellectual disability or developmental delay, abnormalities in MRI, and the presence of dysmorphic features or congenital malformations. Seizure classification followed the 2017 ILAE criteria. Among the 138 patients, 30 (21.7%) exhibited a pathogenic or likely pathogenic variant, with a distribution of 20.7% in males and 22.5% in females. Diagnostic performance correlated with the patient's age at the onset of the first seizure and the type of seizure. Predominant variants were identified in the SCN1A, PRRT2, CDKL5, DEPDC5, TSC2, and SLC2A1 genes. Additionally, 12 genes (CACNA1A, SCN2A, GRIN2A, KCNQ2, CHD2, DYNC1H1, NEXMIF, SCN1B, DDX3X, EEF1A2, NPRL3, UBE3A) exhibited single instances of damage. Notably, novel variants were discovered in DEPDC5, SCN1A, TSC2, CDKL5, NPRL3, DYNC1H1, CHD2, and DDX3X. Identified variants were present in genes previously recognized in both European and non-European populations. A thorough examination of Variants of Uncertain Significance (VUSs), specifically focusing on gene copy number changes, may unveil more extensive chromosomal aberrations. The relatively frequent occurrence of pathological variants in X chromosome-linked genes in girls warrants further investigation, challenging the prevailing notion of male predominance in X-linked epilepsy.

Reanalysis of whole-exome sequencing (WES) data of children with neurodevelopmental disorders in a standard patient care context

This study aims to inform future genetic reanalysis management by evaluating the yield of whole-exome sequencing (WES) reanalysis in standard patient care in the Netherlands. Single-center data of 159 patients with a neurodevelopmental disorder (NDD), in which WES analysis and reanalysis were performed between January 1, 2014, and December 31, 2021, was retrospectively collected. Patients were included if they were under the age of 18 years at initial analysis and if this initial analysis did not result in a diagnosis. Demographic, phenotypic, and genotypic characteristics of patients were collected and analyzed. The primary outcomes of our study were (i) diagnostic yield at reanalysis, (ii) reasons for detecting a new possibly causal variant at reanalysis, (iii) unsolicited findings, and (iv) factors associated with positive result of reanalysis. In addition, we conducted a questionnaire study amongst the 7 genetic department in the Netherlands creating an overview of used techniques, yield, and organization of WES reanalysis. The single-center data show that in most cases, WES reanalysis was initiated by the clinical geneticist (65%) or treating physician (30%). The mean time between initial WES analysis and reanalysis was 3.7 years. A new (likely) pathogenic variant or VUS with a clear link to the phenotype was found in 20 initially negative cases, resulting in a diagnostic yield of 12.6%. In 75% of these patients, the diagnosis had clinical consequences, as for example, a screening plan for associated signs and symptoms could be devised. Most (32%) of the (likely) causal variants identified at WES reanalysis were discovered due to a newly described gene-disease association. In addition to the 12.6% diagnostic yield based on new diagnoses, reclassification of a variant of uncertain significance found at initial analysis led to a definite diagnosis in three patients. Diagnostic yield was higher in patients with dysmorphic features compared to patients without clear dysmorphic features (yield 27% vs. 6%; p = 0.001).Conclusions: Our results show that WES reanalysis in patients with NDD in standard patient care leads to a substantial increase in genetic diagnoses. In the majority of newly diagnosed patients, the diagnosis had clinical consequences. Knowledge about the clinical impact of WES reanalysis, clinical characteristics associated with higher yield, and the yield per year after a negative WES in larger clinical cohorts is warranted to inform guidelines for genetic reanalysis. These guidelines will be of great value for pediatricians, pediatric rehabilitation specialists, and pediatric neurologists in daily care of patients with NDD.What is Known:• Whole exome sequencing can cost-effectively identify a genetic cause of intellectual disability in about 30–40% of patients.• WES reanalysis in a research setting can lead to a definitive diagnosis in 10–20% of previously exome negative cases.What is New:• WES reanalysis in standard patient care resulted in a diagnostic yield of 13% in previously exome negative children with NDD.• The presence of dysmorphic features is associated with an increased diagnostic yield of WES reanalysis.

Persistent SARS-CoV-2 infection in patients seemingly recovered from COVID-19.

SARS-CoV-2 infection is clinically heterogeneous, ranging from asymptomatic to deadly. A few patients with COVID-19 appear to recover from acute viral infection but nevertheless progress in their disease and eventually die, despite persistent negativity at molecular tests for SARS-CoV-2 RNA. Here, we performed post-mortem analyses in 27 consecutive patients who had apparently recovered from COVID-19 but had progressively worsened in their clinical conditions despite repeated viral negativity in nasopharyngeal swabs or bronchioalveolar lavage for 11-300 consecutive days (average: 105.5 days). Three of these patients remained PCR-negative for over 9months. Post-mortem analysis revealed evidence of diffuse or focal interstitial pneumonia in 23/27 (81%) patients, accompanied by extensive fibrotic substitution in 13 cases (47%). Despite apparent virological remission, lung pathology was similar to that observed in acute COVID-19 individuals, including micro- and macro-vascular thrombosis (67% of cases), vasculitis (24%), squamous metaplasia of the respiratory epithelium (30%), frequent cytological abnormalities and syncytia (67%), and the presence of dysmorphic features in the bronchial cartilage (44%). Consistent with molecular test negativity, SARS-CoV-2 antigens were not detected in the respiratory epithelium. In contrast, antibodies against both spike and nucleocapsid revealed the frequent (70%) infection of bronchial cartilage chondrocytes and para-bronchial gland epithelial cells. In a few patients (19%), we also detected positivity in vascular pericytes and endothelial cells. Quantitative RT-PCR amplification in tissue lysates confirmed the presence of viral RNA. Together, these findings indicate that SARS-CoV-2 infection can persist significantly longer than suggested by standard PCR-negative tests, with specific infection of specific cell types in the lung. Whether these persistently infected cells also play a pathogenic role in long COVID remains to be addressed. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Woodhouse-Sakati Syndrome with Unique Unreported Previous Findings

We present here at 16 years old a Saudi girl with alopecia which noted since birth and delayed puberty and short stature, dyslipidemia, diabetes and hypothyroidism. Family history was positive for similar complaints. Genetic study shows a mutation at DCAF17 which is known a common founder mutation confirming diagnosis of Woodhouse-Sakati Syndrome. This patient has many unreported findings of hepatic hemangioma, with Hepatomegaly, high indirect bilirubin, high uric acid, focal segmental Glomerulonephritis and low growth hormone level. Presentation of this syndrome may overlap with other important differential diagnosis like autoimmune polyendocrine syndrome, Alopecia-progressive neurological defect (ANE syndrome), and Turner and Mitochondrial disease. In such presentation, the presence of dysmorphic features and low intelligence quotient (IQ) scores, should alert the physician to look for WSS as a possible diagnosis.

Phenotypic variance in children with chromosomal aberrations – A cohort study

Background: Chromosomal abnormalities are the result of alterations in the number or structure of chromosomes leading to significant human morbidity and mortality. They are responsible for large proportion of miscarriages, developmental delay, disorders of sexual development, congenital malformations, and mental retardation. Objectives: The objectives of the study were to find the occurrence of chromosomal abnormalities in infants and children with various phenotypic presentations and to analyze the impact of associated risk factors for chromosomal abnormalities in children. Materials and Methods: A retrospective single-center study, based on the outcome data of chromosomal analysis of 112 children admitted to the pediatric department of our hospital over a period of 3 years, was reported. The data were collected from the electronic medical records for analysis, including maternal age, consanguinity, family history of any congenital anomalies and malformations, clinical details, and the results of chromosomal analysis. Results: A statistically significant association between the presence of dysmorphic features and chromosomal abnormalities with 3 times increased risk when compared to children with no dysmorphism (relative risk [RR] 3.06, 95% confidence interval [CI] 1.71–5.50, p=0.0002). Among the congenital anomalies, the presence of congenital heart defects had strong association and was found to be 43% higher in children with chromosomal abnormalities (RR 1.43, 95% CI 1.10–1.86, p=0.0069). Our study demonstrated a strong association for maternal age >35 years and the risk for chromosomal abnormality. It was 1.75 times more than the children born to mothers ?35 years age (RR 1.75, 95% CI 1.29–2.36, p=0.0003). Conclusion: Cytogenetics has a major role in diagnosis of chromosomal abnormalities, especially in children with dysmorphic features and congenital heart defects. The early diagnosis is important for planning and resource allocation of specialized health services directed toward the families and infants.

A Comprehensive Clinical Genetics Approach to Critical Congenital Heart Disease in Infancy

To investigate the frequency of genetic diagnoses among infants with critical congenital heart disease (CHD) using a comprehensive cardiovascular genetics approach and to identify genotype-phenotype correlations. A retrospective chart review of patients evaluated by cardiovascular genetics in a pediatric cardiac intensive care unit from 2010 to 2015 was performed. Infants with CHD who were <1month of age were included. CHD was classified using structured phenotype definitions. Cardiac and noncardiac phenotypes were tested for associations with abnormal genetic testing using χ1 and Fisher exact tests. Genetic evaluation was completed in 293 infants with CHD, of whom 213 had isolated congenital heart disease (iCHD) and 80 had multiple congenital anomalies. Overall, the yield of abnormal genetic testing was 26%. The multiple congenital anomalies cohort had a greater yield of genetic testing (39%) than the iCHD cohort (20%) (OR 2.7). Using a non-hierarchical CHD classification and excluding 22q11.2 deletion and common aneuploidies, right ventricular obstructive defects were associated with abnormal genetic testing (P=.0005). Extracardiac features associated with abnormal genetic testing included ear, nose, and throat (P=.003) and brain (P=.0001) abnormalities. A diagnosis of small for gestational age or intrauterine growth retardation also was associated with abnormal genetic testing (P=.0061), as was presence of dysmorphic features (P=.0033, OR 3.5). Infants without dysmorphia with iCHD or multiple congenital anomalies had similar frequencies of abnormal genetic testing. The present study provides evidence to support a comprehensive cardiovascular genetics approach in evaluating infants with critical CHD while also identifying important genotype-phenotype considerations.

Problem hypogonadyzmu ze szczególnym uwzględnieniem problemu u dziewcząt

Hypogonadism is understood as a gonadal defect; it can occur in all periods of life – in embryos, pre-adolescent and post-adolescent children, as well as after menopause. The initial cause of hypogonadism may lie in a pathology of gonads (primary, gonadal, hypergonadotropic hypogonadism) or of the hypothalamic-pituitary system (secondary hypogonadism, hypogonadotrophic hypogonadism). Hypogonadism should be discussed together with the problem of delayed puberty. In all children with delayed puberty, genetic testing with karyotype evaluation is advisable. It is also necessary to exclude pituitary hormone deficiency, especially in children having undergone radiotherapy and/or chemotherapy; it is also necessary to exclude chronic and autoimmune diseases, with special attention brought to the presence of dysmorphic features or anosmia. Molecular studies are also of importance. Guidelines for management of hypogonadism in girls have been presented.

Utility of genetic evaluation in infants with congenital heart defects admitted to the cardiac intensive care unit.

Congenital heart defects (CHDs) are heterogeneous and present with a spectrum of severity, with roughly 25% of patients requiring intervention before age 1. The etiology of disease is unknown in many individuals; however, there is a rapidly expanding understanding of genetic risk factors that may contribute to pathogenesis. Through this work, we sought to evaluate the diagnostic yield of a clinical genetics evaluation and associated genetic testing among infants with critical CHDs. Furthermore, we aimed to both determine the utility of microarray and establish a strong baseline that can be used in future studies of the impact of exome sequencing in this population. We completed a retrospective chart review of 364 infants with CHDs admitted to the Cardiac Intensive Care Unit who underwent a clinical genetics evaluation. A genetic diagnosis was established in 25% of patients: 9% of infants were diagnosed prenatally, while 16% were diagnosed postnatally. Cardiac lesion subtype greatly influenced the diagnostic yield. On physical exam, the presence of dysmorphic features, as assessed by a clinical geneticist, was associated with a sevenfold increased likelihood of reaching a diagnosis. Directed by clinical acumen, diagnostic rates varied by testing modality with rates of 23% for karyotype, 12% for fluorescent in situ hybridization or multiplex-dependent ligation probe analysis, 9% for genome wide microarray, and 17% for targeted gene sequencing. Careful consideration of lesion subtype and physical exam findings clarify populations of infants with CHD that benefit from a genetics evaluation and inform an efficient testing paradigm. © 2016 Wiley Periodicals, Inc.

Infantile presentation and rapid progression of coarctation of aorta in a case of Williams syndrome

Williams syndrome is a multisystem disorder caused by the deletion of multiple genes on chromosome 7. Many patients are identified through presence of dysmorphic features and associated cardiac abnormalities. Cardiovascular abnormalities in Williams syndrome is characterized by presence of supravalvular aortic stenosis which is most common followed by pulmonary artery stenosis, mitral valve prolapse, aortic hypoplasia, coarctation of aorta, and septal defects. Usually, these obstructive lesions are mild and do not present in infancy and progress slowly. If severe in infantile age-group, they often require surgery. We are reporting a case of Williams syndrome who presented with heart failure demonstrating supravalvular aortic stenosis (a common feature of Williams syndrome) and rapidly progressive coarctation of aorta with refractory symptoms.

Use of Dysmorphology for Subgroup Classification on Autism Spectrum Disorder in Chinese Children

Data from 1,261 Chinese Autistic Spectrum Disorder (ASD) patients were evaluated and categorized into dysmorphic (10.79%) and non-dysmorphic groups (89.21%) upon physical examination by the presence of dysmorphic features. Abnormal MRI/CT result, IQ scores and epilepsy were significantly associated with the dysmorphic group of ASD children. However, gender, EEG abnormality and family history and recurrence of ASD were not found to be significantly different between group statuses. It is suggested that results collected from the Chinese population generally resembles that found in the Caucasians with ethnical differences still present. Current study supports the result shown in Miles' study (Miles et al. in Am J Med Genet 135A:171-180, 2005), in which heterogeneity subtypes of autism of different genetic origins which could be distinguished by presence of dysmorphic features on the patients.

Predicting Responsiveness to Treatment of Children With Autism

This retrospective study examined predictors of outcome for children With autism folloWing 6 and 12 months of early intensive behavioral intervention. Potential predictor variables included pretreatment functioning, age at onset of treatment, treatment intensity, family involvement, and physical characteristics (e.g., brain abnormalities, dysmorphology). For the 19 study participants, presence of dysmorphic features Was the only variable that predicted response to treatment after 6 months ( R2 = .58). Dysmorphology Was associated With Worse outcomes. After 12 months, both dysmorphology and a history of regression predicted poorer response to treatment ( R2 = .67). Children Who made the most progress in treatment had pretreatment language skills and normal physical features. Dysmorphic features in children With autism may represent abnormalities in prenatal development that are associated With poorer child outcomes.

Turner’s syndrome: A growing concern

Turner’s syndrome: A growing concern

Prevalence of developmental enamel defects in children with cerebral palsy.

Enamel defects observed in primary anterior teeth of 123 children with congenital cerebral palsy (CP) born 1983 through 1985 in four northern California counties were categorized using an adaptation of the Developmental Defects of Enamel Index. Nineteen children (15%) had crowns or loss of tooth substance (LTS) due to attrition. Missing enamel (ME) including horizontal groove, was observed in 39 children (32%). Twenty-four children without ME (20%) had enamel pits, vertical grooves, or colored enamel opacities. Forty-one (33%) had clinically normal enamel. ME children did not differ significantly from those with normal enamel with respect to race, sex, singleton vs twin, severity or type of CP, or presence of dysmorphic features. ME children more often had shorter gestational ages than children with normal enamel. More ME children, even those who were not low in birth weight, were reported by parents to have required neonatal intensive care.

Congenital Brain Anomalies Associated With the Hypoplastic Left Heart Syndrome

This study details the type, frequency, and clinical presentation of developmental brain anomalies in 41 infants with the hypoplastic left heart syndrome encountered during a 52-month interval. Overall, 29% of the infants had either a major or minor central nervous system abnormality. Overt central nervous system malformations, including 3 cases of agenesis of the corpus callosum and 1 case of holoprosencephaly, were seen in 4 infants (10%). Micrencephaly (brain weight at autopsy more than 2 SDs below the mean for age) was found in 27% of the infants. An immature cortical mantle was seen in 21% of the study group. Seven infants (17%) had specific recognizable patterns of malformation. The absence of dysmorphic physical features did not preclude overt or subtle central nervous system malformations. Conversely, the presence of dysmorphic features did not reliably indicate an underlying brain anomaly. Infants who had hypoplastic left heart syndrome as one of multiple nonneurologic malformations were more likely to have micrencephaly than those infants with hypoplastic left heart syndrome as an isolated abnormality. Occurrence of developmental neuropathology was elevated in those infants with hypoplastic left heart syndrome who did not have a recognizable pattern of malformation but who were small for gestational age, microcephalic, or had ocular abnormalities. Infants with hypoplastic left heart syndrome deserve careful genetic, opthalmologic, and neurologic evaluations, imaging of their intracranial anatomy, and long-term neurologic follow-up.