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- Rodriguez-Palmero, Agusti, et al.
(författare)
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DLG4-related synaptopathy : a new rare brain disorder
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:5, s. 888-899
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Tidskriftsartikel (refereegranskat)abstract
- PurposePostsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.MethodsThe clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing.ResultsThe clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit–hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies.ConclusionThe present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
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- Buchanan, James, et al.
(författare)
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Factor's that impact on women's decision-making around prenatal genomic tests : An international discrete choice survey
- 2022
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Ingår i: Prenatal Diagnosis. - : John Wiley & Sons. - 0197-3851 .- 1097-0223. ; 42:7, s. 934-946
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Tidskriftsartikel (refereegranskat)abstract
- Objective We conducted a survey-based discrete-choice experiment (DCE) to understand the test features that drive women's preferences for prenatal genomic testing, and explore variation across countries. Methods Five test attributes were identified as being important for decision-making through a literature review, qualitative interviews and quantitative scoring exercise. Twelve scenarios were constructed in which respondents choose between two invasive tests or no test. Women from eight countries who delivered a baby in the previous 24 months completed a DCE presenting these scenarios. Choices were modeled using conditional logit regression analysis. Results Surveys from 1239 women (Australia: n = 178; China: n = 179; Denmark: n = 88; Netherlands: n = 177; Singapore: n = 90; Sweden: n = 178; UK: n = 174; USA: n = 175) were analyzed. The key attribute affecting preferences was a test with the highest diagnostic yield (p < 0.01). Women preferred tests with short turnaround times (p < 0.01), and tests reporting variants of uncertain significance (VUS; p < 0.01) and secondary findings (SFs; p < 0.01). Several country-specific differences were identified, including time to get a result, who explains the result, and the return of VUS and SFs. Conclusion Most women want maximum information from prenatal genomic tests, but our findings highlight country-based differences. Global consensus on how to return uncertain results is not necessarily realistic or desirable.
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- Hammond, J, et al.
(författare)
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Assessing women's preferences towards tests that may reveal uncertain results from prenatal genomic testing: Development of attributes for a discrete choice experiment, using a mixed-methods design
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:1, s. e0261898-
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Tidskriftsartikel (refereegranskat)abstract
- Prenatal DNA tests, such as chromosomal microarray analysis or exome sequencing, increase the likelihood of receiving a diagnosis when fetal structural anomalies are identified. However, some parents will receive uncertain results such as variants of uncertain significance and secondary findings. We aimed to develop a set of attributes and associated levels for a discrete-choice experiment (DCE) that will examine parents’ preferences for tests that may reveal uncertain test results. A two phase mixed-methods approach was used to develop attributes for the DCE. In Phase 1, a “long list” of candidate attributes were identified via two approaches: 1) a systematic review of the literature around parental experiences of uncertainty following prenatal testing; 2) 16 semi-structured interviews with parents who had experienced uncertainty during pregnancy and 25 health professionals who return uncertain prenatal results. In Phase 2, a quantitative scoring exercise with parents prioritised the candidate attributes. Clinically appropriate levels for each attribute were then developed. A final set of five attributes and levels were identified: likelihood of getting a result, reporting of variants of uncertain significance, reporting of secondary findings, time taken to receive results, and who tells you about your result. These attributes will be used in an international DCE study to investigate preferences and differences across countries. This research will inform best practice for professionals supporting parents to manage uncertainty in the prenatal setting.
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- Ilinca, A., et al.
(författare)
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Whole-Exome Sequencing in 22 Young Ischemic Stroke Patients With Familial Clustering of Stroke
- 2020
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Ingår i: Stroke. - : Ovid Technologies (Wolters Kluwer Health). - 0039-2499 .- 1524-4628. ; 51:4, s. 1056-1063
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Tidskriftsartikel (refereegranskat)abstract
- Backgrounds and Purpose-Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods-We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands' clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results-Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2:c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2:c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142:c.148C>G (p.Leu50Val), and PTPRN2:c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10c.1294dupG (p.Val432fs), IKBKB: c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions-Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.
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- Soller, MJ, et al.
(författare)
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How to do genetic counseling in psychiatry?
- 2021
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Ingår i: EUROPEAN PSYCHIATRY. - : Royal College of Psychiatrists. - 0924-9338 .- 1778-3585. ; 64, s. S50-S50
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Genetic counselling has been defined as the process of helping people “understand and adapt to medical, psychosocial, and familial aspects of genetic conditions.” It can also help patients and families deal with stigma and understand the significance of possible genetic findings. Psychiatric genetic counselling (PGC) is an emerging field aimed to help people with a personal or family history of psychiatric illnesses such as schizophrenia, bipolar disorder, or neuropsychiatric conditions, to understand genetic etiological mechanisms as a critical component. Counselling strategies are used to identify and adapt to psychological and familial consequences of the conditions and to reduce stigma surrounding the psychiatric illness. A recent survey showed that PGC is still not routinely offered and usually only discussed at the initiative of the patient, e.g. if they ask about the possibility of “hereditary" illness, or if a caregiver during a session for another indication, identifies the family history. If a monogenetic or chromosomal cause is identified, the genetic counselling follows a more traditional path, but if, on the other hand, the cause is complex, the counselling will not be as clearcut. It will then focus on explaining risk for disease with quite uncertain riskscores as no causative genetic change is identified. Although genetic testing most often cannot be offered and individual risk scores based on genetic markers cannot be given, there is still great value for patients and their relatives in PGC. Studies have shown that the effect of PGC is an increase of empowerment and a reduction of stigma.No significant relationships.
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