ORCID Profile
0000-0003-3285-4281
Current Organisations
Sahlgrenska University Hospital
,
Karolinska University Hospital
,
Karolinska Universitetssjukhuset
,
Karolinska Institutet
,
University of Gothenburg
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Publisher: Elsevier BV
Date: 11-2016
Publisher: Elsevier BV
Date: 05-2015
Publisher: Wiley
Date: 26-04-2013
DOI: 10.1111/CGE.12081
Abstract: Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Publisher: BMJ
Date: 18-11-2020
DOI: 10.1136/JMEDGENET-2020-107385
Abstract: Germline pathogenic variants in DICER1 cause DICER1 syndrome, an autosomal dominant, pleiotropic tumour predisposition syndrome with variable expressivity and reduced penetrance for specific dysplastic and neoplastic lesions. Recently, a syndrome with the acronym GLOW ( G lobal developmental delay, L ung cysts, O vergrowth, W ilms tumour) was described in two children with mosaic missense mutations in hotspot residues of the DICER1 RNase IIIb domain. Whole genome sequencing, exome sequencing, Sanger sequencing, digital PCR and a review of Wilms tumours with DICER1 RNase III domain mutations were performed. A de novo heterozygous c.4031C T (p.S1344L) variant in the sequence encoding the RNase IIIa domain of DICER1 was detected. Clinical investigations revealed a phenotype that resembles the GLOW subphenotype of DICER1 syndrome. The phenotypic overlap between patients with p.S1344L mutation and GLOW syndrome provide clinical support for recent discoveries that RNase IIIa-Ser1344 site mutations impede miRNA-5p biogenesis analogous to DICER1 hotspot mutations in the RNase IIIb domain. We show that an in idual with a heterozygous germline p.S1344L mutation has a severe form of DICER1 syndrome (‘DICER1 syndrome plus’), with notable features of intellectual disability, macrocephaly, physical abnormalities, Wilms tumour and a well-differentiated fetal adenocarcinoma of the lung.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2017
DOI: 10.1038/NG.3792
Publisher: Springer Science and Business Media LLC
Date: 21-10-2020
DOI: 10.1038/S41467-020-19289-5
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Springer Science and Business Media LLC
Date: 23-12-2020
Publisher: Elsevier BV
Date: 02-2016
Publisher: Springer Science and Business Media LLC
Date: 10-2020
DOI: 10.1038/S41467-020-18723-Y
Abstract: Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case–control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance ( p 1.25E−06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5% e.g., GABRG2 and UIMC1 ) of which, 61 reach FWER significance ( p 3.64E−07 e.g., CASZ1 ). In addition to doubling the number of patients for many NDD risk genes, we present phenotype–genotype correlations for seven risk genes ( CTCF , HNRNPU , KCNQ3 , ZBTB18 , TCF12 , SPEN , and LEO1 ) based on this large-scale targeted sequencing effort.
Publisher: Springer Science and Business Media LLC
Date: 31-08-2011
DOI: 10.1038/NATURE10406
Publisher: Springer Science and Business Media LLC
Date: 20-10-2004
Abstract: Kabuki syndrome (KS) is a rare multiple congenital anomaly/mental retardation syndrome. It is characterized by a distinct facial appearance, mental retardation, postnatal growth retardation, skeletal anomalies, unusual dermatoglyphics and fetal fingertip pads. It has previously been speculated that KS is caused by a microdeletion or duplication. In a recent report, an interstitial microduplication of 8p22-23.1 was presented in several cases with this disorder. We investigated 10 Caucasian patients diagnosed with KS by fluorescence in situ hybridization and microsatellite markers located on 8p22-23.1. Using the same clones that were previously reported to be duplicated on chromosome 8p, we could exclude the duplication in all our patients. In addition, we performed a genome-wide screening on this group of patients using array-based comparative genomic hybridization containing BAC clones spaced at approximately 1 Mb intervals across the genome and could not find any evidence for gene dose alterations. The characteristics of KS are variable, a fact that complicates the diagnosis of this disorder. It is possible that we will find genetic heterogeneity among Kabuki patients, and therefore it is unlikely that all patients have an interstitial 8p duplication. We conclude that the etiology of KS remains to be solved and further genetic studies are necessary to delineate its genetic cause.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-09-2929
Abstract: CSDE1 disruptive mutations are associated with autism.
No related grants have been discovered for Ann Nordgren.