RÉSUMÉ
An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
Sujet(s)
Exome , Gènes , Maladies génétiques congénitales/diagnostic , Mutation , Analyse de séquence d'ADN , Canada , Enfant , Maladies génétiques congénitales/génétique , Séquençage nucléotidique à haut débit , HumainsSujet(s)
Nanisme/génétique , Hyperostose corticale infantile/génétique , Hypocalcémie/génétique , Récepteurs viraux/génétique , Adulte , Enfant d'âge préscolaire , Nanisme/anatomopathologie , Femelle , Humains , Hyperostose corticale infantile/anatomopathologie , Hypocalcémie/anatomopathologie , Nouveau-né , MutationRÉSUMÉ
Whole-exome sequencing (WES) has proven its utility in finding novel genes associated with rare conditions and its usefulness is being further demonstrated in expanding the phenotypes of well known diseases. We present here a family with a previously undiagnosed X-linked condition characterized by progressive restriction of joint range of motion, prominence of the supraorbital ridge, audiology issues and hernias. They had an average stature, normal occipitofrontal circumference and intelligence, absence of dysostosis multiplex and otherwise good health. A diagnosis of Hunter syndrome was determined using WES and further supported by biochemical investigations. The phenotype of this family does not correspond to either the severe or attenuated clinical subtypes of Hunter syndrome. As further atypical families are reported, this classification will need to be modified. Our findings highlight the utility of WES in expanding the recognized phenotypic spectrum of known syndromes.
Sujet(s)
Exome/génétique , Mucopolysaccharidose de type II/génétique , Analyse de séquence d'ADN , Adulte , Enfant , Enfant d'âge préscolaire , Famille , Femelle , Humains , Nourrisson , Mâle , Mucopolysaccharidose de type II/imagerie diagnostique , Mutation/génétique , Pedigree , Phénotype , Radiographie , Reproductibilité des résultats , Crâne/imagerie diagnostiqueRÉSUMÉ
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease that predominantly affects the right ventricle and is associated with ventricular arrhythmias that may lead to sudden cardiac death. Mutations within at least seven separate genes have been identified to cause ARVC, however a genetic culprit remains elusive in approximately 50% of cases. Although negative genetic testing may be secondary to pathogenic mutations within undiscovered genes, an alternative explanation may be the presence of large deletions or duplications involving known genes. These large copy number variants may not be detected with standard clinical genetic testing which is presently limited to direct DNA sequencing. We describe two cases of ARVC possessing large deletions involving plakophilin-2 (PKP2) identified with microarray analysis and/or multiplex ligation-dependent probe amplification (MLPA) that would have been classified as genotype negative with standard clinical genetic testing. A deletion of the entire coding region of PKP2 excluding exon 1 was identified in patient 1 and his son. In patient 2, MLPA analysis of PKP2 revealed deletion of the entire gene with subsequent microarray analysis demonstrating a de novo 7.9 Mb deletion of chromosome 12p12.1p11.1. These findings support screening for large copy number variants in clinically suspected ARVC cases without clear disease causing mutations following initial sequencing analysis.
Sujet(s)
Dysplasie ventriculaire droite arythmogène/génétique , Délétion de gène , Plakophilines/génétique , Adulte , Dysplasie ventriculaire droite arythmogène/diagnostic , Électroencéphalographie , Exons , Ordre des gènes , Humains , Mâle , MutationRÉSUMÉ
We describe the identification and clinical presentation of four individuals from three unrelated families with hemizygous deletions involving the DPYD gene at chromosome 1p21.3. DPYD encodes dihydropyrimidine dehydrogenase, which is the initial and rate-limiting enzyme in the catabolism of pyrimidine bases. All four individuals described met diagnostic criteria for autism spectrum disorder with severe speech delay. Patient 1's deletion was originally reported in 2008, and more detailed clinical information is provided. Subsequently, this male individual was found to have a missense mutation in the X-linked PTCHD1 autism susceptibility gene, which may also contribute to the phenotype. Patients 2 and 3 are siblings with a novel deletion encompassing the DPYD gene. In their mother, the genomic region deleted from chromosome 1p21.3 was inserted into chromosome 10. A fourth proband had a novel 10-kb intragenic deletion of exon 6 of the DPYD gene detected on a higher resolution microarray. Our study suggests that hemizygous deletions involving the DPYD locus present with variable phenotypes which can include speech delay and autistic features, and may also be influenced by additional mutations in other genes, issues which need to be considered in genetic counseling.
Sujet(s)
Troubles généralisés du développement de l'enfant/génétique , Chromosomes humains de la paire 1/génétique , Dihydrouracil dehydrogenase (NADP)/génétique , Adolescent , Adulte , Enfant , Enfant d'âge préscolaire , Délétion de segment de chromosome , Chromosomes humains de la paire 10/génétique , Femelle , Humains , Mâle , PedigreeRÉSUMÉ
Prenatal exposure to alcohol can result in a spectrum of adverse developmental outcomes, collectively termed fetal alcohol spectrum disorders (FASDs). This study evaluated deficits in sensory, motor and cognitive processing in children with FASD that can be identified using eye movement testing. Our study group was composed of 89 children aged 8-15 years with a diagnosis within the FASD spectrum [i.e. fetal alcohol syndrome (FAS), partial fetal alcohol syndrome (pFAS), and alcohol-related neurodevelopmental disorder (ARND)], and 92 controls. Subjects looked either towards (prosaccade) or away from (antisaccade) a peripheral target that appeared on a computer monitor, and eye movements were recorded with a mobile, video-based eye tracker. We hypothesized that: (i) differences in the magnitude of deficits in eye movement control exist across the three diagnostic subgroups; and (ii) children with FASD display a developmental delay in oculomotor control. Children with FASD had increased saccadic reaction times (SRTs), increased intra-subject variability in SRTs, and increased direction errors in both the prosaccade and antisaccade tasks. Although development was associated with improvements across tasks, children with FASD failed to achieve age-matched control levels of performance at any of the ages tested. Moreover, children with ARND had faster SRTs and made fewer direction errors in the antisaccade task than children with pFAS or FAS, although all subgroups were different from controls. Our results demonstrate that eye tracking can be used as an objective measure of brain injury in FASD, revealing behavioral deficits in all three diagnostic subgroups independent of facial dysmorphology.
Sujet(s)
Mesures des mouvements oculaires , Mouvements oculaires/physiologie , Troubles du spectre de l'alcoolisation foetale/physiopathologie , Adolescent , Facteurs âges , Enfant , Femelle , Humains , Mâle , Grossesse , Temps de réaction/physiologie , Facteurs sexuelsRÉSUMÉ
BACKGROUND: Chronic prenatal alcohol exposure causes a spectrum of deleterious effects in offspring, collectively termed fetal alcohol spectrum disorders (FASD), and deficits in executive function are prevalent in FASD. The goal of this research was to test the hypothesis that children with FASD exhibit performance deficits in tasks that assess attention, planning and spatial working memory. METHODS: Subjects (8-15 years male and female children) with a diagnosis of fetal alcohol syndrome (FAS), partial FAS (pFAS), or alcohol-related neurodevelopmental disorder (ARND), and age- and sex-matched controls, completed four tasks selected from the Cambridge Neuropsychological Tests Automated Battery (CANTAB). RESULTS: Compared with age-matched control children (n = 92), subjects with FASD (n = 89) exhibited longer reaction and decision times (effect size range; Cohen's d = .51 to .73), suggesting deficits in attention. Children with FASD demonstrated deficits in planning and spatial working memory that became more pronounced when task difficulty increased. The largest effect size in this study population (Cohen's d = 1.1) occurred in the spatial working memory task. Only one outcome measure revealed differences across the diagnostic subgroups, although all groups were different from control. CONCLUSION: This study demonstrates that deficits in multiple executive function domains, including set shifting, planning and strategy use, attention and spatial working memory, can be assessed in children with FASD using an easy to administer, brief battery of computer-based neuropsychological tasks. The tasks appear to be equally sensitive for brain injury resulting from prenatal exposure to alcohol, regardless of the presence of facial dysmorphology.
Sujet(s)
Troubles de la cognition/diagnostic , Troubles de la cognition/épidémiologie , Traitement automatique des données , Troubles du spectre de l'alcoolisation foetale/épidémiologie , Troubles de la mémoire/diagnostic , Troubles de la mémoire/épidémiologie , Tests neuropsychologiques , Adolescent , Encéphale/physiopathologie , Lésions encéphaliques/épidémiologie , Enfant , Incapacités de développement/épidémiologie , Incapacités de développement/physiopathologie , Diagnostic assisté par ordinateur , Femelle , État de santé , Humains , Mâle , Mémoire à court terme , Troubles mentaux/diagnostic , Troubles mentaux/épidémiologie , Grossesse , Effets différés de l'exposition prénatale à des facteurs de risque/épidémiologie , Temps de réaction , Indice de gravité de la maladie , Perception de l'espace , Perception visuelleRÉSUMÉ
BACKGROUND: Mutations in the E-cadherin (CDH1) gene are a well documented cause of hereditary diffuse gastric cancer (HDGC). Development of evidence based guidelines for CDH1 screening for HDGC have been complicated by its rarity, variable penetrance, and lack of founder mutations. METHODS: Forty three new gastric cancer (GC) families were ascertained from multiple sources. In 42 of these families at least one gastric cancer was pathologically confirmed to be a diffuse gastric cancer (DGC); the other family had intestinal type gastric cancers. Screening of the entire coding region of the CDH1 gene and all intron/exon boundaries was performed by bi-directional sequencing. RESULTS: Novel mutations were found in 13 of the 42 DGC families (31% overall). Twelve of these mutations occur among the 25 families with multiple cases of gastric cancer and with pathologic confirmation of diffuse gastric cancer phenotype in at least one individual under the age of 50 years. The mutations found include small insertions and deletions, splice site mutations, and three non-conservative amino acid substitutions (A298T, W409R, and R732Q). All three missense mutations conferred loss of E-cadherin function in in vitro assays. Multiple cases of breast cancers including pathologically confirmed lobular breast cancers were observed both in mutation positive and negative families. CONCLUSION: Germline truncating CDH1 mutations are found in 48% of families with multiple cases of gastric cancer and at least one documented case of DGC in an individual under 50 years of age. We recommend that these criteria be used for selecting families for CDH1 mutational analysis.