uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Annerén, Göran
Alternative names
Publications (10 of 62) Show all publications
Gudmundsson, S., Annerén, G., Marcos-Alcalde, Í., Wilbe, M., Melin, M., Gómez-Puertas, P. & Bondeson, M.-L. (2019). A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4: Review of the literature. European Journal of Medical Genetics, 62(6), Article ID 103526.
Open this publication in new window or tab >>A novel RAD21 p.(Gln592del) variant expands the clinical description of Cornelia de Lange syndrome type 4: Review of the literature
Show others...
2019 (English)In: European Journal of Medical Genetics, ISSN 1769-7212, E-ISSN 1878-0849, Vol. 62, no 6, article id 103526Article in journal (Refereed) Published
Abstract [en]

Cornelia de Lange syndrome (CdLS) is a heterogeneous developmental disorder where 70% of clinically diagnosed patients harbor a variant in one of five CdLS associated cohesin proteins. Around 500 variants have been identified to cause CdLS, however only eight different alterations have been identified in the RAD21 gene, encoding the RAD21 cohesin complex component protein that constitute the link between SMC1A and SMC3 within the cohesin ring. We report a 15-month-old boy presenting with developmental delay, distinct CdLS-like facial features, gastrointestinal reflux in early infancy, testis retention, prominent digit pads and diaphragmatic hernia. Exome sequencing revealed a novel RAD21 variant, c.1774_1776del, p.(Gln592del), suggestive of CdLS type 4. Segregation analysis of the two healthy parents confirmed the variant as de novo and bioinformatic analysis predicted the variant as disease-causing. Assessment by in silico structural model predicted that the p.Gln592del variant results in a discontinued contact between RAD21-Lys591 and the SMC1A residues Glu1191 and Glu1192, causing changes in the RAD21-SMC1A interface. In conclusion, we report a patient that expands the clinical description of CdLS type 4 and presents with a novel RAD21 p.(Glu592del) variant that causes a disturbed RAD21-SMC1A interface according to in silco structural modeling.

Place, publisher, year, edition, pages
Elsevier, 2019
Keywords
Cohesin complex, Cohesin protein, Cohesinopathy, Cornelia de Lange syndrome type 4, RAD21 cohesin complex component
National Category
Genetics Health Sciences
Identifiers
urn:nbn:se:uu:diva-379362 (URN)10.1016/j.ejmg.2018.08.007 (DOI)000470115000001 ()30125677 (PubMedID)
Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-06-26Bibliographically approved
Wester Oxelgren, U., Westerlund, J., Myrelid, Å., Annerén, G., Johansson, L., Åberg, M., . . . Frenell, E. (2019). An intervention targeting social, communication and daily activity skills in children and adolescents with Down syndrome and autism: a pilot study. Neuropsychiatric Disease and Treatment, 15, 2049-2056
Open this publication in new window or tab >>An intervention targeting social, communication and daily activity skills in children and adolescents with Down syndrome and autism: a pilot study
Show others...
2019 (English)In: Neuropsychiatric Disease and Treatment, ISSN 1176-6328, E-ISSN 1178-2021, Vol. 15, p. 2049-2056Article in journal (Refereed) Published
Abstract [en]

Purpose: To evaluate whether an intervention, targeting deficits in social communication, interaction and restricted activities in children and adolescents with Down syndrome and autism could lead to enhanced participation in family and school activities.

Methods: The intervention included education for parents and school staff about autism, and workshops to identify social-communication and daily living activities that would be meaningful for the child to practice at home and at school. Thereafter, a three-month period of training for the child followed. Outcome measures comprised evaluation of goal achievement for each child, the “Family Strain Index” questionnaire and a visual scale pertaining to the parents´ general opinion about the intervention.

Results: On average, more than 90% of the goals were (to some extent or completely) achieved at home and at school. The mean scores of the “Family Strain Index” were almost identical at the follow-up to those before intervention. The evaluation supported that the use of strategies, intended to facilitate activities and communication, remained largely 18 months after start of the intervention.

Conclusion: Despite the group involved in this study being comprised of older children and adolescents, most of whom had severe and profound intellectual disability, the goal achievements and parents’ views on the intervention were encouraging.

National Category
Pediatrics
Research subject
Pediatrics
Identifiers
urn:nbn:se:uu:diva-381069 (URN)10.2147/NDT.S205721 (DOI)000476857800001 ()31410008 (PubMedID)
Available from: 2019-04-04 Created: 2019-04-04 Last updated: 2019-08-30Bibliographically approved
Frisk, S., Taylan, F., Blaszczyk, I., Nennesmo, I., Annerén, G., Herm, B., . . . Nordgren, A. (2019). Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth. Clinical Genetics, 96(2), 118-125
Open this publication in new window or tab >>Early activating somatic PIK3CA mutations promote ectopic muscle development and upper limb overgrowth
Show others...
2019 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 96, no 2, p. 118-125Article in journal (Refereed) Published
Abstract [en]

PIK3CA-related overgrowth spectrum is a group of rare genetic disorders with asymmetric overgrowth caused by somatic mosaic PIK3CA mutations. Here, we report clinical data and molecular findings from two patients with congenital muscular upper limb overgrowth and aberrant anatomy. During debulking surgery, numerous ectopic muscles were found in the upper limbs of the patients. DNA sequencing, followed by digital polymerase chain reaction, was performed on DNA extracted from biopsies from hypertrophic ectopic muscles and identified the somatic mosaic PIK3CA hotspot mutations c.3140A > G, p.(His1047Arg) and c.1624G > A, p.(Glu542Lys) in a male (patient 1) and a female (patient 2) patient, respectively. Patient 1 had four ectopic muscles and unilateral isolated muscular overgrowth while patient 2 had 13 ectopic muscles and bilateral isolated muscular overgrowth of both upper limbs, indicating that her mutation occurred at early pre-somitic mesoderm state. The finding of PIK3CA mutations in ectopic muscles highlights the importance of PIK3CA in cell fate in early human embryonic development. Moreover, our findings provide evidence that the disease phenotype depends on the timing of PIK3CA mutagenesis during embryogenesis and confirm the diagnostic entity PIK3CA-related muscular overgrowth with ectopic accessory muscles.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
accessory, cell fate, ectopic, muscle hypertrophy, muscular hypertrophy, PIK3CA, PROS
National Category
Clinical Laboratory Medicine
Identifiers
urn:nbn:se:uu:diva-390499 (URN)10.1111/cge.13543 (DOI)000474933200002 ()30919936 (PubMedID)
Funder
Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilSwedish Research CouncilBerth von Kantzows foundationThe Swedish Brain FoundationStockholm County Council
Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2019-08-12Bibliographically approved
Angius, A., Uva, P., Oppo, M., Buers, I., Persico, I., Onano, S., . . . Crisponi, L. (2019). Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses. Clinical Genetics, 95(5), 607-614
Open this publication in new window or tab >>Exome sequencing in Crisponi/cold-induced sweating syndrome-like individuals reveals unpredicted alternative diagnoses
Show others...
2019 (English)In: Clinical Genetics, ISSN 0009-9163, E-ISSN 1399-0004, Vol. 95, no 5, p. 607-614Article in journal (Refereed) Published
Abstract [en]

Crisponi/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder characterized by a complex phenotype (hyperthermia and feeding difficulties in the neonatal period, followed by scoliosis and paradoxical sweating induced by cold since early childhood) and a high neonatal lethality. CS/CISS is a genetically heterogeneous disorder caused by mutations in CRLF1 (CS/CISS1), CLCF1 (CS/CISS2) and KLHL7 (CS/CISS-like). Here, a whole exome sequencing approach in individuals with CS/CISS-like phenotype with unknown molecular defect revealed unpredicted alternative diagnoses. This approach identified putative pathogenic variations in NALCN, MAGEL2 and SCN2A. They were already found implicated in the pathogenesis of other syndromes, respectively the congenital contractures of the limbs and face, hypotonia, and developmental delay syndrome, the Schaaf-Yang syndrome, and the early infantile epileptic encephalopathy-11 syndrome. These results suggest a high neonatal phenotypic overlap among these disorders and will be very helpful for clinicians. Genetic analysis of these genes should be considered for those cases with a suspected CS/CISS during neonatal period who were tested as mutation negative in the known CS/CISS genes, because an expedited and corrected diagnosis can improve patient management and can provide a specific clinical follow-up.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
Crisponi, cold-induced sweating syndrome, CRLF1, MAGEL2, NALCN, SCN2A, whole exome sequencing
National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-382813 (URN)10.1111/cge.13532 (DOI)000465027000008 ()30859550 (PubMedID)
Available from: 2019-05-07 Created: 2019-05-07 Last updated: 2019-05-07Bibliographically approved
Wester Oxelgren, U., Myrelid, Å., Annerén, G., Westerlund, J., Gustafsson, J. & Fernell, E. (2019). More severe intellectual disability found in teenagers compared to younger children with Down syndrome.. Acta Paediatrica, 108(5), 961-966
Open this publication in new window or tab >>More severe intellectual disability found in teenagers compared to younger children with Down syndrome.
Show others...
2019 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 108, no 5, p. 961-966Article in journal (Refereed) Published
Abstract [en]

AIM: We investigated the severities and profiles of intellectual disability (ID) in a population-based group of children with Down syndrome and related the findings to coexisting autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD).

METHODS: There were about 100 children with Down syndrome living in Uppsala County, Sweden, at the time of the study who all received medical services from the same specialist outpatient clinic. The 60 children (68% male) were aged 5-17 years at inclusion: 41 were assessed within the study and 19 had test results from previous assessments, performed within three years before inclusion. We compared two age groups: 5-12 and 13-18 years old.

RESULTS: Of the 60 children, 49 were assessed with a cognitive test and the 11 children who could not participate in formal tests had clinical assessments. Mild ID was found in 9% of the older children and in 35% of the younger children. Severe ID was found in 91% of the older children and 65% of the younger children. Verbal and nonverbal domains did not differ.

CONCLUSION: Intellectual level was lower in the older children and patients with Down syndrome need to be followed during childhood with regard to their ID levels.

Keywords
Attention deficit hyperactivity disorder, Autism spectrum disorder, Cognitive profile, Down syndrome, Intellectual disability
National Category
Pediatrics
Identifiers
urn:nbn:se:uu:diva-380997 (URN)10.1111/apa.14624 (DOI)000465091200027 ()30372566 (PubMedID)
Available from: 2019-04-03 Created: 2019-04-03 Last updated: 2019-05-14Bibliographically approved
Gudmundsson, S., Wilbe, M., Gorniok, B. F., Molin, A.-M., Ekvall, S., Johansson, J., . . . Bondeson, M.-L. (2019). TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish. Scientific Reports, 9, Article ID 10730.
Open this publication in new window or tab >>TAF1, associated with intellectual disability in humans, is essential for embryogenesis and regulates neurodevelopmental processes in zebrafish
Show others...
2019 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 10730Article in journal (Refereed) Published
Abstract [en]

The TATA-box binding protein associated factor 1 (TAF1) protein is a key unit of the transcription factor II D complex that serves a vital function during transcription initiation. Variants of TAF1 have been associated with neurodevelopmental disorders, but TAF1's molecular functions remain elusive. In this study, we present a five-generation family affected with X-linked intellectual disability that co-segregated with a TAF1 c. 3568C>T, p.(Arg1190Cys) variant. All affected males presented with intellectual disability and dysmorphic features, while heterozygous females were asymptomatic and had completely skewed X-chromosome inactivation. We investigated the role of TAF1 and its association to neurodevelopment by creating the first complete knockout model of the TAF1 orthologue in zebrafish. A crucial function of human TAF1 during embryogenesis can be inferred from the model, demonstrating that intact taf1 is essential for embryonic development. Transcriptome analysis of taf1 zebrafish knockout revealed enrichment for genes associated with neurodevelopmental processes. In conclusion, we propose that functional TAF1 is essential for embryonic development and specifically neurodevelopmental processes.

Keywords
taf1, intellectual disability, zebrafish
National Category
Genetics
Research subject
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-379358 (URN)10.1038/s41598-019-46632-8 (DOI)000476874600028 ()31341187 (PubMedID)
Funder
EU, European Research Council, 241995
Note

Title in Thesis list of papers: TAF1, associated with intellectual disability in humans, is essential for life and regulates neurodevelopmental processes in zebrafish

Available from: 2019-03-15 Created: 2019-03-15 Last updated: 2019-09-23Bibliographically approved
Sobol, M., Klar, J., Laan, L., Shahsavani, M., Schuster, J., Annerén, G., . . . Dahl, N. (2019). Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions. Molecular Neurobiology, 56(10), 7113-7127
Open this publication in new window or tab >>Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions
Show others...
2019 (English)In: Molecular Neurobiology, ISSN 0893-7648, E-ISSN 1559-1182, Vol. 56, no 10, p. 7113-7127Article in journal (Refereed) Published
Abstract [en]

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters. DNA replication, synaptic maturation and neuroactive clusters were disturbed at the early differentiation time point accompanied by a skewed transition from the neural progenitor cell stage and reduced cellular growth. With differentiation, growth factor and extracellular matrix, oxidative phosphorylation and glycolysis emerged as major perturbed clusters. Furthermore, we identified a marked dysregulation of a set of genes encoded by chromosome 21 including an early upregulation of the hub gene APP, supporting its role for disturbed neurogenesis, and the transcription factors OLIG1, OLIG2 and RUNX1, consistent with deficient myelination and neuronal differentiation. Taken together, our findings highlight novel sequential and differentiation-dependent dynamics of disturbed functions, pathways and elements in T21 neurogenesis, providing further insights into developmental abnormalities of the DS brain.

Keywords
Down syndrome, Induced pluripotent stem cells (iPSC), Neural differentiation, RNA sequencing, Proteome profiling
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-395428 (URN)10.1007/s12035-019-1585-3 (DOI)000486010800032 ()30989628 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2015-4870Knut and Alice Wallenberg FoundationAstraZenecaScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Swedish Brain Foundation, FO2018-0100
Available from: 2019-10-23 Created: 2019-10-23 Last updated: 2019-10-23Bibliographically approved
Wilbe, M., Gudmundsson, S., Johansson, J., Ameur, A., Stattin, E.-L., Annerén, G., . . . Bondeson, M.-L. (2017). A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders. Prenatal Diagnosis, 37(11), 1146-1154
Open this publication in new window or tab >>A novel approach using long-read sequencing and ddPCR to investigate gonadal mosaicism and estimate recurrence risk in two families with developmental disorders
Show others...
2017 (English)In: Prenatal Diagnosis, ISSN 0197-3851, E-ISSN 1097-0223, Vol. 37, no 11, p. 1146-1154Article in journal (Refereed) Published
Abstract [en]

Objective

De novo mutations contribute significantly to severe early-onset genetic disorders. Even if the mutation is apparently de novo, there is a recurrence risk due to parental germ line mosaicism, depending on in which gonadal generation the mutation occurred.

Methods

We demonstrate the power of using SMRT sequencing and ddPCR to determine parental origin and allele frequencies of de novo mutations in germ cells in two families whom had undergone assisted reproduction.

Results

In the first family, a TCOF1 variant c.3156C>T was identified in the proband with Treacher Collins syndrome. The variant affects splicing and was determined to be of paternal origin. It was present in <1% of the paternal germ cells, suggesting a very low recurrence risk. In the second family, the couple had undergone several unsuccessful pregnancies where a de novo mutation PTPN11 c.923A>C causing Noonan syndrome was identified. The variant was present in 40% of the paternal germ cells suggesting a high recurrence risk.

Conclusions

Our findings highlight a successful strategy to identify the parental origin of mutations and to investigate the recurrence risk in couples that have undergone assisted reproduction with an unknown donor or in couples with gonadal mosaicism that will undergo preimplantation genetic diagnosis.

National Category
Medical Genetics
Identifiers
urn:nbn:se:uu:diva-342916 (URN)10.1002/pd.5156 (DOI)000415897200012 ()28921562 (PubMedID)
Funder
Swedish Society for Medical Research (SSMF)
Available from: 2018-02-26 Created: 2018-02-26 Last updated: 2019-03-17Bibliographically approved
Wester Oxelgren, U., Myrelid, Å., Annerén, G., Ekstam, B., Göransson, C., Holmbom, A., . . . Fernell, E. (2017). Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study. Developmental Medicine & Child Neurology, 59(3), 276-283
Open this publication in new window or tab >>Prevalence of autism and attention-deficit-hyperactivity disorder in Down syndrome: a population-based study
Show others...
2017 (English)In: Developmental Medicine & Child Neurology, ISSN 0012-1622, E-ISSN 1469-8749, Vol. 59, no 3, p. 276-283Article in journal (Refereed) Published
Abstract [en]

AIM To investigate the prevalence of autism spectrum disorder (ASD) and attention-deficit-hyperactivity disorder (ADHD) in a population-based group of children and adolescents with Down syndrome, and to relate the findings to level of intellectual disability and to medical conditions. METHOD From a population-based cohort of 60 children and adolescents with Down syndrome, 41 individuals (29 males, 12 females; mean age 11y, age range 5-17y) for whom parents gave consent for participation were clinically assessed with regard to ASD and ADHD. The main instruments used were the Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, Swanson, Nolan, and Pelham-IV Rating Scale, and the Adaptive Behavior Assessment System-II. RESULTS High rates of ASD and ADHD were found: 17 (42%) and 14 (34%) of the 41 children met DSM criteria for ASD and ADHD respectively. INTERPRETATION Children with Down syndrome and coexisting neurodevelopmental/neuropsychiatric disorders in addition to intellectual disability and medical disorders constitute a severely disabled group. Based on the results, we suggest that screening is implemented for both ASD and ADHD, at the age of 3 to 5 years and early school years respectively, to make adequate interventions possible.

Place, publisher, year, edition, pages
WILEY, 2017
National Category
Neurology Pediatrics
Identifiers
urn:nbn:se:uu:diva-320266 (URN)10.1111/dmcn.13217 (DOI)000397320200012 ()27503703 (PubMedID)
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2019-04-12Bibliographically approved
Ternby, E., Axelsson, O., Annerén, G., Lindgren, P. & Ingvoldstad, C. (2016). Why do pregnant women accept or decline prenatal diagnosis for Down syndrome?. Journal of community genetics, 7(3), 237-242
Open this publication in new window or tab >>Why do pregnant women accept or decline prenatal diagnosis for Down syndrome?
Show others...
2016 (English)In: Journal of community genetics, ISSN 1868-310X, Vol. 7, no 3, p. 237-242Article in journal (Refereed) Published
Abstract [en]

To investigate if actual knowledge of Down syndrome (DS), influences the decision to accept or decline prenatal diagnosis (PND). Secondary aims were to elucidate reasons for accepting or declining PND and investigate differences between the accepting and declining group in perceived information, knowing someone with DS and thoughts about decision-making. A questionnaire was completed by 76 pregnant women who underwent invasive testing and 65 women who declined tests for chromosomal aberrations in Uppsala, Sweden. Apart from one question no significant differences were found in knowledge of DS between women declining or accepting PND for DS. Both groups had varying and in several respects low levels of knowledge about DS and its consequences. Most common reasons to accept PND were 'to ease my worries' and 'to do all possible tests to make sure the baby is healthy'. Corresponding statements declining PND were 'termination of pregnancy is not an option' and 'because invasive tests increase the risk of miscarriage'. More women declining PND knew someone with DS. Knowledge of DS at these levels is not a major factor when women decide to accept or decline PND for DS. Their choice is mostly based on opinions and moral values.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-300828 (URN)10.1007/s12687-016-0272-6 (DOI)000386778700007 ()27438596 (PubMedID)
Available from: 2016-08-15 Created: 2016-08-15 Last updated: 2016-12-07Bibliographically approved
Organisations

Search in DiVA

Show all publications