Dubowitz syndrome was described in 1965 as a recognizable syndrome characterized by microcephaly, short stature, eczema, mild developmental delays, and an increased risk of malignancy. Since its ...original description, there have been over 200 reported cases though no single gene has been identified to explain a significant proportion of affected individuals. Since the last definitive review of Dubowitz syndrome in 1996, there have been 63 individuals with a clinical, or suspected, diagnosis of Dubowitz syndrome reported in 51 publications. These individuals show a markedly wide spectrum with respect to growth, facial gestalt, psychomotor development, and risk of malignancy; genetic causes were identified in 33% (21/63). Seven individuals had deleterious copy number variants, in particular deletions at 14q32 and 17q24 were reported and showed overlap with the Dubowitz phenotype. Several cases were shown to have single gene disorders that included de novo or biallelic pathogenic variants in several genes including NSUN2 and LIG4 frequently identified by next‐generation sequencing methods. It appears that the inability to identify a single gene responsible for Dubowitz syndrome reflects its extreme clinical and genetic heterogeneity. However, detailed phenotyping combined with careful grouping of subsets of unsolved cases and in conjunction with data‐sharing will identify novel disease genes responsible for additional cases. In the interim, for those clinically diagnosed with a Dubowitz phenotype, we recommend assessment by a Medical Geneticist, a microarray and, if available, clinical or research based genome‐wide sequencing. Management suggestions, including decisions regarding malignancy screening in select patients will be discussed.
Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30–40% of known genetic syndromes. Here, we determine whether syndromes can be ...diagnosed from 3D images of human faces.
We analyzed variation in three-dimensional (3D) facial images of 7057 subjects: 3327 with 396 different syndromes, 727 of their relatives, and 3003 unrelated, unaffected subjects. We developed and tested machine learning and parametric approaches to automated syndrome diagnosis using 3D facial images.
Unrelated, unaffected subjects were correctly classified with 96% accuracy. Considering both syndromic and unrelated, unaffected subjects together, balanced accuracy was 73% and mean sensitivity 49%. Excluding unrelated, unaffected subjects substantially improved both balanced accuracy (78.1%) and sensitivity (56.9%) of syndrome diagnosis. The best predictors of classification accuracy were phenotypic severity and facial distinctiveness of syndromes. Surprisingly, unaffected relatives of syndromic subjects were frequently classified as syndromic, often to the syndrome of their affected relative.
Deep phenotyping by quantitative 3D facial imaging has considerable potential to facilitate syndrome diagnosis. Furthermore, 3D facial imaging of “unaffected” relatives may identify unrecognized cases or may reveal novel examples of semidominant inheritance.
We provide a description of the diagnostic odyssey for a cohort of children seeking diagnosis of a rare genetic disorder in terms of the time from initial consultation to most recent visit or receipt ...of diagnosis, the number of tests per patient, and the types of tests received.
Retrospective chart review of 299 children seen at the Alberta Children's Hospital (ACH) Genetics Clinic (GC) for whom the result of at least one single-gene test, gene panel, or chromosome microarray analysis (CMA) was recorded.
Of 299 patients, 90 (30%) received a diagnosis in the period of the review. Patients had an average of 5.4 tests each; 236 (79%) patients received CMA; 172 (58%) patients received single-gene tests and 34 (11%) received gene panels; 167 (56%) underwent imaging/electrical activity studies. The mean observation period was 898 days (95% confidence interval CI 791, 1004). Among patients with visits recorded prior to visiting ACH GC, 43% of the total observation time occurred prior to the GC.
As genomic technologies expand, the nature of the diagnostic odyssey will change. This study has outlined the current standard of care in the ACH GC, providing a baseline against which future changes can be assessed.
Exome sequencing (ES) can rapidly identify disease-causing variants responsible for rare, single-gene diseases, and potentially reduce the duration of the diagnostic odyssey. Our study examines how ...parents and families value ES.
We developed a discrete choice experiment (DCE) survey that was administered to parents of children with rare diseases. The DCE included 14 choice tasks with 6 attributes and 3 alternatives. A valuation-space model was used to estimate willingness to pay, willingness to wait for test results, and minimum acceptable chance of a diagnosis for changes in each attribute.
There were n = 319 respondents of whom 89% reported their child had genetic testing, and 66% reported their child had a diagnosis. Twenty-six percent reported that their child had been offered ES. Parents were willing to pay CAD$6590 (US$4943), wait 5.2 years to obtain diagnostic test results, and accept a reduction of 3.1% in the chance of a diagnosis for ES compared with operative procedures.
Timely access to ES could reduce the diagnostic odyssey and associated costs. Before ES is incorporated routinely into care for patients with rare diseases in Canada and more broadly, there must be a clear understanding of its value to patients and families.
Dubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported ...with Dubowitz or a “Dubowitz‐like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome‐wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy‐number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next‐generation sequencing. Overall, the DubS‐like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype.
The purpose of this study was to determine if a donor age effect exists for the frequency of aneuploidy and other chromosome abnormalities in human spermatozoa. Sperm samples were collected from 18 ...healthy men from the general population. Each individual belonged to one of six age groups (20-24, 25-29, 30-34, 35-39, 40-44, > or = 45 years) with three men in each group. Two multicolour fluorescence in-situ hybridizations were performed on spermatozoa from each donor using probes for chromosomes 13 and 21, and two chromosome 1-specific probes allowed for detection of duplications and deletions as well as disomy of chromosome 1. The abnormality frequencies and the Pearson correlation coefficients were calculated to determine if a relationship existed between donor age and the frequency of chromosome abnormalities in spermatozoa. A statistically significant association with donor age was detected for the frequency of acentric fragments of chromosome 1 (P < 0.05).
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