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1.	Halgren, Christina, et al. (författare) Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B 2012 Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 82:3, s. 248-255 Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum ranging from severe intellectual disability to normal cognitive function. The etiology is expected to be genetic in as much as 30-50% of the cases, but the underlying genetic cause remains unknown in the majority of cases. By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype. Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype-genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism. Our findings emphasize that ARID1B is important in human brain development and function in general, and in the development of CC and in speech development in particular.
2.	Winberg, Johanna, et al. (författare) Chimerism Resulting From Parthenogenetic Activation and Dispermic Fertilization 2010 Ingår i: American Journal of Medical Genetics, Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 152A:9, s. 2277-2286 Tidskriftsartikel (refereegranskat)abstract Whole-body human chimerism is the result of two zygotes giving rise to one individual, and is a rarely detected condition. We have studied the molecular background and discuss the likely mechanism for the chimerism in a patient with a 46,XX/47,XY,+14 karyotype and ambiguous genitalia, cryptorchidism, pigment anomalies, and normal psychomotor development. We have used karyotyping, interphase-FISH and array-CGH analysis as well as molecular analysis of polymorphic markers from 48 loci in order to define the origin and percentage of 47,XY,+14 cells in different tissues. Based on the findings of two paternal alleles and the detection of homozygous maternal alleles without evidence of crossing-over, and the fact that four alleles were never detected, our results indicate that the chimerism in our patient is the result of dispermic fertilization of a parthenogenetically activated oocyte. Our report underlines that cytogenetic findings suggesting mosaicism might actually indicate chimerism as an underlying mechanism in patients. It also highlights the difficulties in predicting the clinical outcome in patients with genetic aberrations in mosaic or chimeric form.
3.	Anderlid, Britt-Marie (författare) Cryptic chromosome abnormalities in idiopathic mental retardation 2002 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract Mental retardation is a common disorder, affecting 1-3% of the population. In spite of improved diagnostic tools, the etiology can still not be established in half of the cases. Several lines of evidence indicate a genetic origin in a significant number of individuals with idiopathic mental retardation. The subtelomeric regions are gene rich, difficult to analyze with conventional cytogenetic methods and are often involved in rearrangements. Recent investigations have demonstrated subtelomeric abnormalities in a significant proportion of cases with idiopathic MR. We analyzed 111 individuals with idiopathic MR using subtelomeric FISH probes. Ten cryptic subtelomeric rearrangements were found (9%) - five de novo deletions, one unbalanced de novo translocation, three unbalanced inherited translocations and one unbalanced inherited recombinant chromosome. Dysmorphic features were present in all patients with detected subtelomeric rearrangements. In addition, fifty of the patients were screened for interstitial rearrangements with spectral karyotyping, but no aberrations could be found. However, spectral karyotyping could detect the subtelomeric rearrangement in three of the four unbalanced translocations. Two cases with detected cryptic subtelomeric deletions were further analyzed with FISH to determine the size of the deletions and to identify the genes involved. The deletion of terminal 6p was 1.8 Mb, and encompassed five characterized genes. Two of the deleted genes were forkhead transcription factors, members of a gene family involved in embryonic development of different tissues, body axis and midline structures. The size of the terminal 22q deletion was estimated to 100 kb, and three genes were affected by the deletion. ProSAP2, expressed in brain and involved in the cytoskeleton at excitatory synapses, was disrupted in the patient and constitute a strong candidate gene for the 22q13 deletion phenotype. Two isochromosomes, i(9p) and i(9q) were detected in a healthy woman with repeated miscarriages. Analysis with polymorphic DNA markers of the woman and her parents demonstrated maternal unipatental disomy 9. Since the woman was healthy, despite the fact that she lacks paternal genes from chromosome 9, this case supports the theory of absence of maternally imprinted genes on chromosome 9. Twelve patients with supernumerary ring chromosomes were analyzed with micro-FISH, and the exact origin was established. In addition, in eight of the families, microsatellite analysis was performed, and in one patient maternal uniparental disomy 9 was detected. In this case, the symptoms probably are correlated to the presence of the supernumerary ring chromosome, since there seems to be no maternally imprinted genes on chromosome 9. One case of uniparental disomy found in eight analyzed families also supports the theory of marker chromosomes affecting meiotic segregation. The result of this study supports the clinical use of subtelomeric FISH screening in individuals with idiopathic MR. The detection of an inherited rearrangement gives the extended family . the option of carrier detection and prenatal diagnosis. Detailed characterization of chromosome aberrations makes gene identification and genotypelphenotype correlation on gene level possible.
4.	Bena, Frederique, et al. (författare) Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature 2013 Ingår i: American Journal of Medical Genetics Part B. - : Wiley. - 1552-4841 .- 1552-485X. ; 162B:4, s. 388-403 Tidskriftsartikel (refereegranskat)abstract This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the -isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders.
5.	Bremer, Anna, et al. (författare) Copy number variation characteristics in subpopulations of patients with autism spectrum disorders. 2011 Ingår i: American Journal of Medical Genetics, Part B, Neuropsychiatric Genetics. - : Wiley. - 1552-4841. ; 156B156:2, s. 115-124 Tidskriftsartikel (refereegranskat)abstract Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P=0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs
6.	Eriksson, Mats Anders, et al. (författare) First-degree relatives of young children with autism spectrum disorders: some gender aspects. 2012 Ingår i: Research in Developmental Disabilities. - : Elsevier BV. - 0891-4222 .- 1873-3379. ; 33:5, s. 1642-1648 Tidskriftsartikel (refereegranskat)abstract Prenatal risk factors, with special focus on gender distribution of neurodevelopmental and psychiatric conditions were analysed in first-degree relatives in a population-based group of young children with autism spectrum disorders (ASD). Multiple information sources were combined. This group was contrasted with the general population regarding data from the Swedish Medical Birth register. In the ASD group, information was also obtained at parental interviews focusing on developmental and psychiatric disorders in the family. Compared to the general population, fathers of children with ASD were older and parents more often of non-European origin. Mothers of children with ASD had an increased rate of antidepressant and psychoactive medication use, and of scheduled caesarean sections. Fathers and brothers of children with ASD had high rates of ASD including the broader phenotype. Mothers of children with ASD had high rates of depression and other psychiatric disorders. These findings, hypothetically, could reflect a different ASD phenotype and difficulties diagnosing ASD in females or be an example of the close genetic relation between ASD and other psychiatric disorders. The results suggest that, in clinical and research settings, the familial background in ASD should be reviewed with a broader approach, and not be restricted to "looking out" only for diagnoses and symptoms traditionally accepted as being part of or typical of ASD. The high rate of parents of non-European origin has been noted in many Swedish studies of ASD, but the reason for this association, remains unclear.
7.	Eriksson, Mats Anders, et al. (författare) Rare copy number variants are common in young children with autism spectrum disorder 2015 Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 104:6, s. 610-618 Tidskriftsartikel (refereegranskat)abstract AimSeveral studies have suggested that rare copy number variants (CNVs) are an important genetic contributor to autism spectrum disorders. The aims of the study were to use chromosomal microarray to investigate the presence of rare copy number variants in a population-based cohort of well-characterised young children with autism spectrum disorders and to relate the genetic results to neurodevelopmental profiles and medical conditions. MethodsWe performed chromosomal microarray on samples from 162 children who had been referred to the Stockholm Autism Centre for Young Children in Sweden after being diagnosed with autism spectrum disorder between 20 and 54months of age. ResultsPathogenic aberrations were detected in 8.6% of the children and variants of uncertain significance were present in another 8.6%. CNVs were more frequent in children with congenital malformations or dysmorphic features as well as in the subgroup with intellectual disability. ConclusionOur results support the use of chromosomal microarray methods for the first tier genetic analysis of autism spectrum disorder. However, it is likely in the near future that chromosomal microarray methods will probably be replaced by whole-exome and whole-genome sequencing technologies in clinical genetic testing.
8.	Gazdagh, Gabriella, et al. (författare) Extending the phenotypes associated with TRIO gene variants in a cohort of 25 patients and review of the literature 2023 Ingår i: American Journal of Medical Genetics. Part A. - : Wiley-Blackwell. - 1552-4825 .- 1552-4833. ; 191:7, s. 1722-1740 Forskningsöversikt (refereegranskat)abstract The TRIO gene encodes a rho guanine exchange factor, the function of which is to exchange GDP to GTP, and hence to activate Rho GTPases, and has been described to impact neurodevelopment. Specific genotype-to-phenotype correlations have been established previously describing striking differentiating features seen in variants located in specific domains of the TRIO gene that are associated with opposite effects on RAC1 activity. Currently, 32 cases with a TRIO gene alteration have been published in the medical literature. Here, we report an additional 25, previously unreported individuals who possess heterozygous TRIO variants and we review the literature. In addition, functional studies were performed on the c.4394A > G (N1465S) and c.6244-2A > G TRIO variants to provide evidence for their pathogenicity. Variants reported by the current study include missense variants, truncating nonsense variants, and an intragenic deletion. Clinical features were previously described and included developmental delay, learning difficulties, microcephaly, macrocephaly, seizures, behavioral issues (aggression, stereotypies), skeletal problems including short, tapering fingers and scoliosis, dental problems (overcrowding/delayed eruption), and variable facial features. Here, we report clinical features that have not been described previously, including specific structural brain malformations such as abnormalities of the corpus callosum and ventriculomegaly, additional psychological and dental issues along with a more recognizable facial gestalt linked to the specific domains of the TRIO gene and the effect of the variant upon the function of the encoded protein. This current study further strengthens the genotype-to-phenotype correlation that was previously established and extends the range of phenotypes to include structural brain abnormalities, additional skeletal, dental, and psychiatric issues.
9.	Grigelioniene, Giedre, et al. (författare) Analysis of short stature homeobox-containing gene ( SHOX) and auxological phenotype in dyschondrosteosis and isolated Madelung deformity 2001 Ingår i: Human Genetics. - : Springer Science and Business Media LLC. - 1432-1203 .- 0340-6717. ; 109:5, s. 551-558 Tidskriftsartikel (refereegranskat)abstract Dyschondrosteosis (DCO; also called Leri-Weill syndrome) is a skeletal dysplasia characterised by disproportionate short stature because of mesomelic shortening of the limbs. Madelung deformity is a feature of DCO that is distinctive, variable in expressivity and frequently observed. Mutations of the SHOX (short stature homeobox-containing) gene have been previously described as causative in DCO. Isolated Madelung deformity (IMD) without the clinical characteristics of DCO has also been described in sporadic and a few familial cases but the genetic defect underlying IMD is unknown. In this study, we have examined 28 probands with DCO and seven probands with IMD for mutations in the SHOX gene by using polymorphic CA-repeat analysis, fluorescence in situ hybridisation (FISH), Southern blotting, direct sequencing and fibre-FISH analyses. This was combined with auxological examination of the probands and their family members. Evaluation of the auxological data showed a wide intra- and interfamilial phenotype variability in DCO. Out of 28 DCO probands, 22 (79%) were shown to have mutations in the SHOX gene. Sixteen unrelated DCO families had SHOX gene deletions. Four novel DCO-associated mutations were found in different families. In two additional DCO families, the previously described nonsense mutation (Arg195Stop) was detected. We conclude that mutations in the SHOX gene are the major factor in the pathogenesis of DCO. In a female proband with severe IMD and her unaffected sister, we detected an intrachromosomal duplication of the SHOX gene.
10.	Hofmeister, Wolfgang, et al. (författare) CTNND2-a candidate gene for reading problems and mild intellectual disability. 2015 Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 52:2, s. 111-22 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Cytogenetically visible chromosomal translocations are highly informative as they can pinpoint strong effect genes even in complex genetic disorders.METHODS AND RESULTS: Here, we report a mother and daughter, both with borderline intelligence and learning problems within the dyslexia spectrum, and two apparently balanced reciprocal translocations: t(1;8)(p22;q24) and t(5;18)(p15;q11). By low coverage mate-pair whole-genome sequencing, we were able to pinpoint the genomic breakpoints to 2 kb intervals. By direct sequencing, we then located the chromosome 5p breakpoint to intron 9 of CTNND2. An additional case with a 163 kb microdeletion exclusively involving CTNND2 was identified with genome-wide array comparative genomic hybridisation. This microdeletion at 5p15.2 is also present in mosaic state in the patient's mother but absent from the healthy siblings. We then investigated the effect of CTNND2 polymorphisms on normal variability and identified a polymorphism (rs2561622) with significant effect on phonological ability and white matter volume in the left frontal lobe, close to cortical regions previously associated with phonological processing. Finally, given the potential role of CTNND2 in neuron motility, we used morpholino knockdown in zebrafish embryos to assess its effects on neuronal migration in vivo. Analysis of the zebrafish forebrain revealed a subpopulation of neurons misplaced between the diencephalon and telencephalon.CONCLUSIONS: Taken together, our human genetic and in vivo data suggest that defective migration of subpopulations of neuronal cells due to haploinsufficiency of CTNND2 contribute to the cognitive dysfunction in our patients.
11.	Kvarnung, Malin, et al. (författare) Ataxia in Patients With Bi-Allelic NFASC Mutations and Absence of Full-Length NF186 2019 Ingår i: Frontiers in Genetics. - : Frontiers Media SA. - 1664-8021. ; 10 Tidskriftsartikel (refereegranskat)abstract The etiology of hereditary ataxia syndromes is heterogeneous, and the mechanisms underlying these disorders are often unknown. Here, we utilized exome sequencing in two siblings with progressive ataxia and muscular weakness and identified a novel homozygous splice mutation (c.3020-1G > A) in neurofascin (NFASC). In RNA extracted from fibroblasts, we showed that the mutation resulted in inframe skipping of exon 26, with a deprived expression of the full-length transcript that corresponds to NFASC isoform NF186. To further investigate the disease mechanisms, we reprogrammed fibroblasts from one affected sibling to induced pluripotent stem cells, directed them to neuroepithelial stem cells and finally differentiated to neurons. In early neurogenesis, differentiating cells with selective depletion of the NF186 isoform showed significantly reduced neurite outgrowth as well as fewer emerging neurites. Furthermore, whole-cell patch-clamp recordings of patient-derived neuronal cells revealed a lower threshold for openings, indicating altered Na+ channel kinetics, suggesting a lower threshold for openings as compared to neuronal cells without the NFASC mutation. Taken together, our results suggest that loss of the full-length NFASC isoform NF186 causes perturbed neurogenesis and impaired neuronal biophysical properties resulting in a novel early-onset autosomal recessive ataxia syndrome.
12.	Kvarnung, Malin, et al. (författare) Genomic screening in rare disorders : new mutations and phenotypes, highlighting ALG14 as a novel cause of severe intellectual disability 2018 Ingår i: Clinical Genetics. - : John Wiley & Sons. - 0009-9163 .- 1399-0004. ; 94:6, s. 528-537 Tidskriftsartikel (refereegranskat)abstract We have investigated 20 consanguineous families with multiple children affected by rare disorders. Detailed clinical examinations, exome sequencing of affected as well as unaffected family members and further validation of likely pathogenic variants were performed. In 16/20 families, we identified pathogenic variants in autosomal recessive disease genes (ALMS1, PIGT, FLVCR2, TFG, CYP7B1, ALG14, EXOSC3, MEGF10, ASAH1, WDR62, ASPM, PNPO, ERCC5, KIAA1109, RIPK4, MAN1B1). A number of these genes have only rarely been reported previously and our findings thus confirm them as disease genes, further delineate the associated phenotypes and expand the mutation spectrum with reports of novel variants. We highlight the findings in two affected siblings with splice altering variants in ALG14 and propose a new clinical entity, which includes severe intellectual disability, epilepsy, behavioral problems and mild dysmorphic features, caused by biallelic variants in ALG14.
13.	Lam, Matti, et al. (författare) Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality 2019 Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827 .- 1090-2422. ; 383:1 Tidskriftsartikel (refereegranskat)abstract We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.
14.	Lindstrand, Anna, et al. (författare) From cytogenetics to cytogenomics : whole-genome sequencing as a first-line test comprehensively captures the diverse spectrum of disease-causing genetic variation underlying intellectual disability 2019 Ingår i: Genome Medicine. - : BMC. - 1756-994X. ; 11:1 Tidskriftsartikel (refereegranskat)abstract BackgroundSince different types of genetic variants, from single nucleotide variants (SNVs) to large chromosomal rearrangements, underlie intellectual disability, we evaluated the use of whole-genome sequencing (WGS) rather than chromosomal microarray analysis (CMA) as a first-line genetic diagnostic test.MethodsWe analyzed three cohorts with short-read WGS: (i) a retrospective cohort with validated copy number variants (CNVs) (cohort 1, n=68), (ii) individuals referred for monogenic multi-gene panels (cohort 2, n=156), and (iii) 100 prospective, consecutive cases referred to our center for CMA (cohort 3). Bioinformatic tools developed include FindSV, SVDB, Rhocall, Rhoviz, and vcf2cytosure.ResultsFirst, we validated our structural variant (SV)-calling pipeline on cohort 1, consisting of three trisomies and 79 deletions and duplications with a median size of 850kb (min 500bp, max 155Mb). All variants were detected. Second, we utilized the same pipeline in cohort 2 and analyzed with monogenic WGS panels, increasing the diagnostic yield to 8%. Next, cohort 3 was analyzed by both CMA and WGS. The WGS data was processed for large (>10kb) SVs genome-wide and for exonic SVs and SNVs in a panel of 887 genes linked to intellectual disability as well as genes matched to patient-specific Human Phenotype Ontology (HPO) phenotypes. This yielded a total of 25 pathogenic variants (SNVs or SVs), of which 12 were detected by CMA as well. We also applied short tandem repeat (STR) expansion detection and discovered one pathologic expansion in ATXN7. Finally, a case of Prader-Willi syndrome with uniparental disomy (UPD) was validated in the WGS data.Important positional information was obtained in all cohorts. Remarkably, 7% of the analyzed cases harbored complex structural variants, as exemplified by a ring chromosome and two duplications found to be an insertional translocation and part of a cryptic unbalanced translocation, respectively.ConclusionThe overall diagnostic rate of 27% was more than doubled compared to clinical microarray (12%). Using WGS, we detected a wide range of SVs with high accuracy. Since the WGS data also allowed for analysis of SNVs, UPD, and STRs, it represents a powerful comprehensive genetic test in a clinical diagnostic laboratory setting.
15.	Lindstrand, Anna, et al. (författare) Genome sequencing is a sensitive first-line test to diagnose individuals with intellectual disability 2022 Ingår i: Genetics in Medicine. - : ELSEVIER SCIENCE INC. - 1098-3600 .- 1530-0366. ; 24:11, s. 2296-2307 Tidskriftsartikel (refereegranskat)abstract Purpose: Individuals with intellectual disability (ID) and/or neurodevelopment disorders (NDDs) are currently investigated with several different approaches in clinical genetic diagnostics. Methods: We compared the results from 3 diagnostic pipelines in patients with ID/NDD: genome sequencing (GS) first (N = 100), GS as a secondary test (N = 129), or chromosomal microarray (CMA) with or without FMR1 analysis (N = 421). Results: The diagnostic yield was 35% (GS -first), 26% (GS as a secondary test), and 11% (CMA/FMR1). Notably, the age of diagnosis was delayed by 1 year when GS was performed as a secondary test and the cost per diagnosed individual was 36% lower with GS first than with CMA/FMR1. Furthermore, 91% of those with a negative result after CMA/FMR1 analysis (338 individuals) have not yet been referred for additional genetic testing and remain undiagnosed. Conclusion: Our findings strongly suggest that genome analysis outperforms other testing strategies and should replace traditional CMA and FMR1 analysis as a first-line genetic test in individuals with ID/NDD. GS is a sensitive, time-and cost-effective method that results in a confirmed molecular diagnosis in 35% of all referred patients. (c) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
16.	Lindstrand, Anna, et al. (författare) Molecular and clinical characterization of patients with overlapping 10p deletions 2010 Ingår i: American Journal of Medical Genetics. Part A. - : Wiley. - 1552-4825 .- 1552-4833. ; 152A:5, s. 1233-1243 Tidskriftsartikel (refereegranskat)abstract Chromosome 10p terminal deletions have been associated with DiGeorge phenotype, and within the same genomic region haploinsufficiency of GATA3 causes the HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia). We have performed detailed molecular analysis of four patients with partial overlapping 10p deletions by using FISH-mapping, array-CGH, and custom-designed high-resolution oligonucleotide array. All four patients had mental retardation and speech impairment and three of them showed variable signs of HDR syndrome. In addition, two patients had autistic behaviors and had similar dysmorphic features giving them a striking physical resemblance. A review of the literature identified 10 previously published cases with similar 10p deletions and reliable molecular or molecular cytogenetic mapping data. The combined information of present and previous cases suggests that partial deletions of 10p14-p15 represent a syndrome with a distinct and more severe phenotype than previously assumed. The main characteristics include severe mental retardation, language impairment, autistic behavior, and characteristic clinical features. A critical region involved in mental retardation and speech impairment is defined within 1.6 Mb in 10p15.3. In addition, deletion of 4.3 Mb within 10p14 is associated with autism and characteristic clinical findings.
17.	Mastropasqua, Francesca, et al. (författare) Deficiency of the Heterogeneous Nuclear Ribonucleoprotein U locus leads to delayed hindbrain neurogenesis. 2023 Ingår i: Biology open. - : The Company of Biologists. - 2046-6390. ; 12:10 Tidskriftsartikel (refereegranskat)abstract Genetic variants affecting Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU) have been identified in several neurodevelopmental disorders (NDDs). HNRNPU is widely expressed in the human brain and shows the highest postnatal expression in the cerebellum. Recent studies have investigated the role of HNRNPU in cerebral cortical development, but the effects of HNRNPU deficiency on cerebellar development remain unknown. Here, we describe the molecular and cellular outcomes of HNRNPU locus deficiency during in vitro neural differentiation of patient-derived and isogenic neuroepithelial stem cells with a hindbrain profile. We demonstrate that HNRNPU deficiency leads to chromatin remodeling of A/B compartments, and transcriptional rewiring, partly by impacting exon inclusion during mRNA processing. Genomic regions affected by the chromatin restructuring and host genes of exon usage differences show a strong enrichment for genes implicated in epilepsies, intellectual disability, and autism. Lastly, we show that at the cellular level HNRNPU downregulation leads to an increased fraction of neural progenitors in the maturing neuronal population. We conclude that the HNRNPU locus is involved in delayed commitment of neural progenitors to differentiate in cell types with hindbrain profile.
18.	Nordenskjöld, Agneta, et al. (författare) Medfödda missbildningar-Genetik och Klinik. 2012 Ingår i: Barnmedicin, (red) K.Hanseus, H.Lagercrantz, T. Lindberg.. - Lund : Studentlitteratur. - 9789144076096 ; , s. 227-240 Bokkapitel (övrigt vetenskapligt/konstnärligt)
19.	Pettersson, Maria, et al. (författare) Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity 2017 Ingår i: American Journal of Medical Genetics. Part A. - : John Wiley & Sons. - 1552-4825 .- 1552-4833. ; 173:5, s. 1396-1399 Tidskriftsartikel (refereegranskat)abstract Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.
20.	Schoumans, Jacqueline, et al. (författare) Comprehensive mutational analysis of a cohort of Swedish Cornelia de Lange syndrome patients 2007 Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 15:2, s. 143-149 Tidskriftsartikel (refereegranskat)abstract Cornelia de Lange syndrome (CdLS; OMIM 122470) is a rare multiple congenital anomaly/mental retardation syndrome characterized by distinctive dysmorphic facial features, severe growth and developmental delay and abnormalities of the upper limbs. About 50% of CdLS patients have been found to have heterozygous mutations in the NIPBL gene and a few cases were recently found to be caused by mutations in the X-linked SMC1L1 gene. We performed a mutation screening of all NIPBL coding exons by direct sequencing in 11 patients (nine sporadic and two familial cases) diagnosed with CdLS in Sweden and detected mutations in seven of the cases. All were de novo, and six of the mutations have not been previously described. Four patients without identifiable NIPBL mutations were subsequently subjected to multiplex ligation-dependent probe amplification analysis to exclude whole exon deletions/duplications of NIPBL. In addition, mutation analysis of the 5' untranslated region (5' UTR) of NIPBL was performed. Tiling resolution array comparative genomic hybridization analysis was carried out on these four patients to detect cryptic chromosome imbalances and in addition the boys were screened for SMC1L1 mutations. We found a de novo 9p duplication with a size of 0.6 Mb in one of the patients with a CdLS-like phenotype but no mutations were detected in SMC1L1. So far, two genes (NIPBL and SMC1L1) have been identified causing CdLS or CdLS-like phenotypes. However, in a considerable proportion of individuals demonstrating the CdLS phenotype, mutations in any of these two genes are not found and other potential loci harboring additional CdLS-causing genes should be considered.
21.	Schoumans, Jacqueline, et al. (författare) Genome-wide screening using array-CGH does not reveal microdeletions/microduplications in children with Kabuki syndrome. 2005 Ingår i: Eur J Hum Genet. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 13:2, s. 260-3 Tidskriftsartikel (refereegranskat)
22.	Schuster, Jens, Assistant Professor, 1972-, et al. (författare) Mowat-Wilson syndrome : Generation of two human iPS cell lines (UUIGPi004A and UUIGPi005A) from siblings with a truncating ZEB2 gene variant 2019 Ingår i: Stem Cell Research. - : Elsevier BV. - 1873-5061 .- 1876-7753. ; 39 Tidskriftsartikel (refereegranskat)abstract Mowat-Wilson syndrome (MWS) is a complex developmental syndrome caused by heterozygous mutations in the Zinc finger E-box-binding homeobox 2 gene (ZEB2). We generated the first human iPSC lines from primary fibroblasts of two siblings with MWS carrying a heterozygous ZEB2 stop mutation (c.1027C > T; p.Arg343*) using the Sendai virus reprogramming system. Both iPSC lines were free from reprogramming vector genes, expressed pluripotency markers and showed potential to differentiate into the three germ layers. Genetic analysis confirmed normal karyotypes and a preserved stop mutation. These iPSC lines will provide a useful resource to study altered neural lineage fate and neuropathophysiology in MWS.
23.	Schuster, Jens, Assistant Professor, 1972-, et al. (författare) ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function 2022 Ingår i: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 15 Tidskriftsartikel (refereegranskat)abstract Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2. Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.
24.	Smeds, Henrik, et al. (författare) X-linked Malformation Deafness : Neurodevelopmental Symptoms Are Common in Children With IP3 Malformation and Mutation in POU3F4 2022 Ingår i: Ear and Hearing. - : Lippincott, Williams & Wilkins. - 0196-0202 .- 1538-4667. ; 43:1, s. 53-69 Tidskriftsartikel (refereegranskat)abstract Objective: Incomplete partition type 3 (IP3) malformation deafness is a rare hereditary cause of congenital or rapid progressive hearing loss. The children present with a severe to profound mixed hearing loss and temporal bone imaging show a typical inner ear malformation classified as IP3. Cochlear implantation is one option of hearing restoration in severe cases. Little is known about other specific difficulties these children might exhibit, for instance possible neurodevelopmental symptoms.Material and methods: Ten 2; 0 to 9; 6-year-old children with IP3 malformation deafness (nine boys and one girl) with cochlear implants were evaluated with a retrospective chart review in combination with an additional extensive multidisciplinary assessment day. Hearing, language, cognition, and mental ill-health were compared with a control group of ten 1; 6 to 14; 5-year-old children with cochlear implants (seven boys and three girls) with another genetic cause of deafness, mutations in the GJB2 gene.Results: Mutations in POU3F4 were found in nine of the 10 children with IP3 malformation. Children with IP3 malformation deafness had an atypical outcome with low level of speech recognition (especially in noise), executive functioning deficits, delayed or impaired speech as well as atypical lexical-semantic and pragmatic abilities, and exhibited mental ill-health issues. Parents of children with IP3 malformation were more likely to report that they were worried about their child’s psychosocial wellbeing. Controls, however, had more age-typical results in all these domains. Eight of 10 children in the experimental group had high nonverbal cognitive ability despite their broad range of neurodevelopmental symptoms.Conclusions: While cochlear implantation is a feasible alternative for children with IP3 malformation deafness, co-occurring neurodevelopmental anomalies, such as attention deficit hyperactivity or developmental language disorder, and mental ill-health issues require an extensive and consistent multidisciplinary team approach during childhood to support their overall habilitation.
25.	Tamouza, Ryad, et al. (författare) HLA Polymorphism in Regressive and Non-Regressive Autism: A Preliminary Study. 2020 Ingår i: Autism research : official journal of the International Society for Autism Research. - : Wiley. - 1939-3806. ; 13:2, s. 182-186 Tidskriftsartikel (refereegranskat)abstract Autism spectrum disorders (ASD) comprises heterogeneous neurodevelopmental conditions with symptom onset usually during infancy. However, about 10%-30% of affected cases experience a loss of language and social skills around 18-30months, so-called regressive autism. In this subset with regression, immune dysfunctions including inflammation and autoimmunity have been proposed to be at risk factors. Given the implication of the human histocompatibility antigens (HLA) system in various aspects of immune responses, including autoimmunity, and in ASD, we investigate here the distribution of the HLA Class I and Class II haplotypes in 131 children with ASD meeting DSM-IV TR criteria, with and without regression. We found that 62 of the 98 non-regressive ASD patients carry the HLA-DPA101-DPB104 sub-haplotype as compared to 14 of the 33 patients with regression (63% vs. 43% respectively, Pc =0.02), suggesting that this HLA haplotype may exert a protective effect against regression. Similarly, the HLA-DPA101-DPB104 has also been found to be more represented in healthy controls as compared to patients affected with common nonpsychiatric autoimmune disorders. Overall our findings suggest a possible involvement of HLA polymorphism in the context of regressive ASD. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: Immune dysfunctions including inflammatory and autoimmune processes have been reported in autism, particularly in regressive forms. In this study, we analyzed the distribution of HLA haplotypes among children with autism spectrum disorder (ASD), with and without regression from Sweden and observed that HLA-DPA101-DPB104 sub-haplotype was less represented in patients with regressive autism as compared with those without regression. Such possible protective effect, also observed in other common autoimmune disorders, may constitute a link between HLA-mediated immune processes and regressive ASD.
26.	Zhao, Sen, et al. (författare) Expanding the mutation and phenotype spectrum of MYH3-associated skeletal disorders 2022 Ingår i: NPJ genomic medicine. - : Nature Publishing Group. - 2056-7944. ; 7:1 Tidskriftsartikel (refereegranskat)abstract Pathogenic variants in MYH3 cause distal arthrogryposis type 2A and type 2B3 as well as contractures, pterygia and spondylocarpotarsal fusion syndromes types 1A and 1B. These disorders are ultra-rare and their natural course and phenotypic variability are not well described. In this study, we summarize the clinical features and genetic findings of 17 patients from 10 unrelated families with vertebral malformations caused by dominant or recessive pathogenic variants in MYH3. Twelve novel pathogenic variants in MYH3 (NM_002470.4) were identified: three of them were de novo or inherited in autosomal dominant way and nine were inherited in autosomal recessive way. The patients had vertebral segmentation anomalies accompanied with variable joint contractures, short stature and dysmorphic facial features. There was a significant phenotypic overlap between dominant and recessive MYH3-associated conditions regarding the degree of short stature as well as the number of vertebral fusions. All monoallelic variants caused significantly decreased SMAD3 phosphorylation, which is consistent with the previously proposed pathogenic mechanism of impaired canonical TGF-β signaling. Most of the biallelic variants were predicted to be protein-truncating, while one missense variant c.4244T>G,p.(Leu1415Arg), which was inherited in an autosomal recessive way, was found to alter the phosphorylation level of p38, suggesting an inhibition of the non-canonical pathway of TGF-β signaling. In conclusion, the identification of 12 novel pathogenic variants and overlapping phenotypes in 17 affected individuals from 10 unrelated families expands the mutation and phenotype spectrum of MYH3-associated skeletal disorders. We show that disturbances of canonical or non-canonical TGF-β signaling pathways are involved in pathogenesis of MYH3-associated skeletal fusion (MASF) syndrome.
27.	Zhou, Xiao-Lei, et al. (författare) Association of adenomatous polyposis coli (APC) gene polymorphisms with autism spectrum disorder (ASD). 2007 Ingår i: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics. - : Wiley. - 1552-4841 .- 1552-485X. ; 144B:3, s. 351-354 Tidskriftsartikel (refereegranskat)abstract We serendipitously identified a single nucleotide polymorphism (SNP), 8636C>A (rs1804197) in the 3'-untranslated region of the adenomatous polyposis coli (APC) gene to be associated with autism spectrum disorder (ASD). In order to gain further evidence for the association between the APC locus and ASD, we genotyped four additional adjacent common SNPs (rs2229992, rs42427, rs459552, and rs465899) in the coding regions within the APC gene in a set of Swedish ASDs and controls. One common haplotype TGAG was found to be associated with ASD after haplotype analysis using both Haploview v3.1.1 (P = 0.006) and COCAPHASE v2.403 (P = 0.030). This result is the first to suggest that the genomic locus at APC is associated with ASD, and that the APC gene itself is a good predisposing candidate to be evaluated in future studies due to its important role in neuronal development and function.

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