Publications by authors named "Alessandra Maugeri"

28 Publications

  • Page 1 of 1

Interaction between KDELR2 and HSP47 as a Key Determinant in Osteogenesis Imperfecta Caused by Bi-allelic Variants in KDELR2.

Am J Hum Genet 2020 11 13;107(5):989-999. Epub 2020 Oct 13.

Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam 1081BT, the Netherlands.

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.
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http://dx.doi.org/10.1016/j.ajhg.2020.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675035PMC
November 2020

Collaboration Around Rare Bone Diseases Leads to the Unique Organizational Incentive of the Amsterdam Bone Center.

Front Endocrinol (Lausanne) 2020 11;11:481. Epub 2020 Aug 11.

Amsterdam UMC, Department of Oral and MaxilloFacial Surgery/Oral Pathology, Amsterdam Bone Center, Amsterdam Movement Sciences, Amsterdam, Netherlands.

In the field of rare bone diseases in particular, a broad care team of specialists embedded in multidisciplinary clinical and research environment is essential to generate new therapeutic solutions and approaches to care. Collaboration among clinical and research departments within a University Medical Center is often difficult to establish, and may be hindered by competition and non-equivalent cooperation inherent in a hierarchical structure. Here we describe the "collaborative organizational model" of the Amsterdam Bone Center (ABC), which emerged from and benefited the rare bone disease team. This team is often confronted with pathologically complex and under-investigated diseases. We describe the benefits of this model that still guarantees the autonomy of each team member, but combines and focuses our collective expertise on a clear shared goal, enabling us to capture synergistic and innovative opportunities for the patient, while avoiding self-interest and possible harmful competition.
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http://dx.doi.org/10.3389/fendo.2020.00481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431598PMC
May 2021

Germline variants in HEY2 functional domains lead to congenital heart defects and thoracic aortic aneurysms.

Genet Med 2021 01 21;23(1):103-110. Epub 2020 Aug 21.

Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Purpose: In this study we aimed to establish the genetic cause of a myriad of cardiovascular defects prevalent in individuals from a genetically isolated population, who were found to share a common ancestor in 1728.

Methods: Trio genome sequencing was carried out in an index patient with critical congenital heart disease (CHD); family members had either exome or Sanger sequencing. To confirm enrichment, we performed a gene-based association test and meta-analysis in two independent validation cohorts: one with 2685 CHD cases versus 4370 . These controls were also ancestry-matched (same as FTAA controls), and the other with 326 cases with familial thoracic aortic aneurysms (FTAA) and dissections versus 570 ancestry-matched controls. Functional consequences of identified variants were evaluated using expression studies.

Results: We identified a loss-of-function variant in the Notch target transcription factor-encoding gene HEY2. The homozygous state (n = 3) causes life-threatening congenital heart defects, while 80% of heterozygous carriers (n = 20) had cardiovascular defects, mainly CHD and FTAA of the ascending aorta. We confirm enrichment of rare risk variants in HEY2 functional domains after meta-analysis (MetaSKAT p = 0.018). Furthermore, we show that several identified variants lead to dysregulation of repression by HEY2.

Conclusion: A homozygous germline loss-of-function variant in HEY2 leads to critical CHD. The majority of heterozygotes show a myriad of cardiovascular defects.
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http://dx.doi.org/10.1038/s41436-020-00939-4DOI Listing
January 2021

Phenotypic spectrum of TGFB3 disease-causing variants in a Dutch-French cohort and first report of a homozygous patient.

Clin Genet 2020 05 16;97(5):723-730. Epub 2020 Jan 16.

Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Paris, France.

Disease-causing variants in TGFB3 cause an autosomal dominant connective tissue disorder which is hard to phenotypically delineate because of the small number of identified cases. The purpose of this retrospective cross-sectional multicenter study is to elucidate the genotype and phenotype in an international cohort of TGFB3 patients. Eleven (eight novel) TGFB3 disease-causing variants were identified in 32 patients (17 families). Aortic root dilatation and mitral valve disease represented the most common cardiovascular findings, reported in 29% and 32% of patients, respectively. Dissection involving distal aortic segments occurred in two patients at age 50 and 52 years. A high frequency of systemic features (65% high-arched palate, 63% arachnodactyly, 57% pectus deformity, 52% joint hypermobility) was observed. In familial cases, incomplete penetrance and variable clinical expressivity were noted. Our cohort included the first described homozygous patient, who presented with a more severe phenotype compared to her heterozygous relatives. In conclusion, TGFB3 variants were associated with a high percentage of systemic features and aortic disease (dilatation/dissection) in 35% of patients. No deaths occurred from cardiovascular events or pregnancy-related complications. Nevertheless, homozygosity may be driving a more severe phenotype.
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http://dx.doi.org/10.1111/cge.13700DOI Listing
May 2020

The first family with adult osteogenesis imperfecta caused by a novel homozygous mutation in CREB3L1.

Mol Genet Genomic Med 2019 08 17;7(8):e823. Epub 2019 Jun 17.

Department of Clinical Genetics, Amsterdam Movement Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Osteogenesis imperfecta (OI) is a clinically heterogeneous disease characterized by extreme skeletal fragility. It is caused by mutations in genes frequently affecting collagen biosynthesis. Mutations in CREB3L1 encoding the ER stress transducer OASIS are very rare and are only reported in pediatric patients. We report a large family with a novel CREB3L1 mutation, with severe adult clinical presentation.

Methods: Clinical examination was performed on the family members. Next generation sequencing was performed for the causative genes for OI. The mutation was confirmed in other family members with Sanger sequencing.

Results: A novel homozygous mutation in CREB3L1 was identified in the three affected patients. The parents and siblings who carry the mutation in heterozygous state were clinically unaffected. The three affected siblings, who were reported to have been born healthy, presented very severe progressive skeletal malformations and joint contractures but absence of common OI characteristics including blue sclerae, deafness, and dentinogenesis imperfecta. Resorption of a part of the humerus presumably associated with fracture nonunion and pseudarthrosis.

Conclusion: We report a novel homozygous CREB3L1 mutation in a large Indonesian family; the homozygous affected members have survived to adulthood and they present a more severe phenotype than previously reported, expanding the clinical spectrum of OI for this gene.
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http://dx.doi.org/10.1002/mgg3.823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687637PMC
August 2019

Autosomal dominant Marfan syndrome caused by a previously reported recessive FBN1 variant.

Mol Genet Genomic Med 2019 02 28;7(2):e00518. Epub 2018 Nov 28.

Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Background: Pathogenic variants in FBN1 cause autosomal dominant Marfan syndrome but can also be found in patients presenting with apparently isolated features of Marfan syndrome. Moreover, several families with autosomal recessive Marfan syndrome caused by pathogenic variants in FBN1 have been described. The aim of this report was to underline the clinical variability that can be associated with the pathogenic variant c.1453C>T, p.(Arg485Cys) in FBN1.

Methods: We provide the clinical details of two autosomal dominant families with this specific FBN1 variant, which was previously associated with autosomal recessive Marfan syndrome.

Results: Clinical data of 14 individuals carrying this variant from these two families were collected retrospectively. In both families, the diagnosis of autosomal dominant Marfan syndrome was established based on the characteristics of the variant and the phenotype which includes aortic aneurysms and dissections. Of interest, in one of the families, multiple relatives were diagnosed with early onset abdominal aortic aneurysms.

Conclusion: In conclusion, FBN1 variant c.1453C>T, p.(Arg485Cys) is a pathogenic variant that can cause autosomal dominant Marfan syndrome characterized by a high degree of clinical variability and apparently isolated early onset familial abdominal aortic aneurysms.
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http://dx.doi.org/10.1002/mgg3.518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393656PMC
February 2019

Novel pathogenic variants in five families with arterial aneurysm and dissection: further delineation of the phenotype.

J Med Genet 2019 04 2;56(4):220-227. Epub 2018 Jul 2.

Center of Medical Genetics, Faculty of Medicine and Health Sciences, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Background: Missense variants in , encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.

Objectives: The aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define genotype-phenotype correlations.

Methods And Results: Using gene panel sequencing, we identified a nonsense variant and four missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.

Conclusion: Taken together, our data suggest that heterozygous loss-of-function variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.
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http://dx.doi.org/10.1136/jmedgenet-2018-105304DOI Listing
April 2019

Results of next-generation sequencing gene panel diagnostics including copy-number variation analysis in 810 patients suspected of heritable thoracic aortic disorders.

Hum Mutat 2018 09 12;39(9):1173-1192. Epub 2018 Jul 12.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, the Netherlands.

Simultaneous analysis of multiple genes using next-generation sequencing (NGS) technology has become widely available. Copy-number variations (CNVs) in disease-associated genes have emerged as a cause for several hereditary disorders. CNVs are, however, not routinely detected using NGS analysis. The aim of this study was to assess the diagnostic yield and the prevalence of CNVs using our panel of Hereditary Thoracic Aortic Disease (H-TAD)-associated genes. Eight hundred ten patients suspected of H-TAD were analyzed by targeted NGS analysis of 21 H-TAD associated genes. In addition, the eXome hidden Markov model (XHMM; an algorithm to identify CNVs in targeted NGS data) was used to detect CNVs in these genes. A pathogenic or likely pathogenic variant was found in 66 of 810 patients (8.1%). Of these 66 pathogenic or likely pathogenic variants, six (9.1%) were CNVs not detectable by routine NGS analysis. These CNVs were four intragenic (multi-)exon deletions in MYLK, TGFB2, SMAD3, and PRKG1, respectively. In addition, a large duplication including NOTCH1 and a large deletion encompassing SCARF2 were detected. As confirmed by additional analyses, both CNVs indicated larger chromosomal abnormalities, which could explain the phenotype in both patients. Given the clinical relevance of the identification of a genetic cause, CNV analysis using a method such as XHMM should be incorporated into the clinical diagnostic care for H-TAD patients.
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http://dx.doi.org/10.1002/humu.23565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175145PMC
September 2018

Ehlers Danlos syndrome, kyphoscoliotic type due to Lysyl Hydroxylase 1 deficiency in two children without congenital or early onset kyphoscoliosis.

Eur J Med Genet 2017 Oct 27;60(10):536-540. Epub 2017 Jul 27.

Department of Pediatrics, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands; Department of Medical Genetics, St George's University of London, London, UK.

We report two children with Ehlers Danlos, kyphoscoliotic type confirmed by Lysyl Hydroxylase 1 deficiency due to bi-allelic PLOD1 mutations (kEDS-PLOD1) who were initially thought to have either a diagnosis of classical EDS (cEDS) or a neuromuscular disorder due to absence of (congenital) scoliosis. As the two patients reported here illustrate, patients with kEDS-PLOD1 do not always have a kyphoscoliosis present at birth or in the first year of life, neither do they necessarily develop kyphoscoliosis later in infancy. Using the past criteria for kEDS there was considerable overlap with the clinical diagnostic criteria for EDS classical type. In the patients reported here without (kypho) scoliosis this has delayed the diagnosis, which is unfortunate as the diagnosis of kEDS-PLOD1 results in a different recurrence risk and has management consequences. Interestingly, the new criteria for kEDS would not have prevented this diagnostic delay as congenital or early onset kyphoscoliosis (progressive or non-progressive) is deemed obligatory for the diagnosis of kEDS. Being aware of the limitations of clinical diagnostic criteria, we recommend that (i) in patients without a positive family history nor identified COL5A1/2 mutations, lysyl hydroxylase deficiency or biallelic PLOD1 mutations should be excluded before the diagnosis classical EDS can be made and (ii) PLOD1 and COL5A1/2 should be included in the same Next Generation Sequencing (NGS) gene panel.
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http://dx.doi.org/10.1016/j.ejmg.2017.07.011DOI Listing
October 2017

SMAD2 Mutations Are Associated with Arterial Aneurysms and Dissections.

Hum Mutat 2015 Dec 10;36(12):1145-9. Epub 2015 Sep 10.

Department of Clinical Genetics, Center for Connective Tissue Research, VU University Medical Center, Amsterdam, 1007, MB, The Netherlands.

We report three families with arterial aneurysms and dissections in which variants predicted to be pathogenic were identified in SMAD2. Moreover, one variant occurred de novo in a proband with unaffected parents. SMAD2 is a strong candidate gene for arterial aneurysms and dissections given its role in the TGF-β signaling pathway. Furthermore, although SMAD2 and SMAD3 probably have functionally distinct roles in cell signaling, they are structurally very similar. Our findings indicate that SMAD2 mutations are associated with arterial aneurysms and dissections and are in accordance with the observation that patients with pathogenic variants in genes encoding proteins involved in the TGF-β signaling pathway exhibit arterial aneurysms and dissections as key features.
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http://dx.doi.org/10.1002/humu.22854DOI Listing
December 2015

First genetic analysis of aneurysm genes in familial and sporadic abdominal aortic aneurysm.

Hum Genet 2015 Aug 28;134(8):881-93. Epub 2015 May 28.

Department of Vascular Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

Genetic causes for abdominal aortic aneurysm (AAA) have not been identified and the role of genes associated with familial thoracic aneurysms in AAA has not been explored. We analyzed nine genes associated with familial thoracic aortic aneurysms, the vascular Ehlers-Danlos gene COL3A1 and the MTHFR p.Ala222Val variant in 155 AAA patients. The thoracic aneurysm genes selected for this study were the transforming growth factor-beta pathway genes EFEMP2, FBN1, SMAD3, TGBF2, TGFBR1, TGFBR2, and the smooth muscle cells genes ACTA2, MYH11 and MYLK. Sanger sequencing of all coding exons and exon-intron boundaries of these genes was performed. Patients with at least one first-degree relative with an aortic aneurysm were classified as familial AAA (n = 99), the others as sporadic AAA. We found 47 different rare heterozygous variants in eight genes: two pathogenic, one likely pathogenic, twenty-one variants of unknown significance (VUS) and twenty-three unlikely pathogenic variants. In familial AAA we found one pathogenic and segregating variant (COL3A1 p.Arg491X), one likely pathogenic and segregating (MYH11 p.Arg254Cys), and fifteen VUS. In sporadic patients we found one pathogenic (TGFBR2 p.Ile525Phefs*18) and seven VUS. Thirteen patients had two or more variants. These results show a previously unknown association and overlapping genetic defects between AAA and familial thoracic aneurysms, indicating that genetic testing may help to identify the cause of familial and sporadic AAA. In this view, genetic testing of these genes specifically or in a genome-wide approach may help to identify the cause of familial and sporadic AAA.
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http://dx.doi.org/10.1007/s00439-015-1567-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495250PMC
August 2015

Familial Ehlers-Danlos syndrome with lethal arterial events caused by a mutation in COL5A1.

Am J Med Genet A 2015 Jun 2;167(6):1196-203. Epub 2015 Apr 2.

Department of Medical Genetics, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands.

Different forms of Ehlers-Danlos syndrome (EDS) exist, with specific phenotypes and associated genes. Vascular EDS, caused by heterozygous mutations in the COL3A1 gene, is characterized by fragile vasculature with a high risk of catastrophic vascular events at a young age. Classic EDS, caused by heterozygous mutations in the COL5A1 or COL5A2 genes, is characterized by fragile, hyperextensible skin and joint laxity. To date, vessel rupture in four unrelated classic EDS patients with a confirmed COL5A1 mutation has been reported. We describe familial occurrence of a phenotype resembling vascular EDS in a mother and her two sons, who all died at an early age from arterial ruptures. Diagnostic Sanger sequencing in the proband failed to detect aberrations in COL3A1, COL1A1, COL1A2, TGFBR1, TGFBR2, SMAD3, and ACTA2. Next, the proband's DNA was analyzed using a next-generation sequencing approach targeting 554 genes linked to vascular disease (VASCULOME project). A novel heterozygous mutation in COL5A1 was detected, resulting in an essential glycine substitution at the C-terminal end of the triple helix domain (NM_000093.4:c.4610G>T; p.Gly1537Val). This mutation was also present in DNA isolated from autopsy material of the index's brother. No material was available from the mother, but the mutation was excluded in her parents, siblings and in the father of her sons, suggesting that the COL5A1 mutation occurred in the mother's genome de novo. In conclusion, we report familial occurrence of lethal arterial events caused by a COL5A1 mutation.
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http://dx.doi.org/10.1002/ajmg.a.36997DOI Listing
June 2015

Beneficial Outcome of Losartan Therapy Depends on Type of FBN1 Mutation in Marfan Syndrome.

Circ Cardiovasc Genet 2015 Apr 22;8(2):383-8. Epub 2015 Jan 22.

From the Departments of Cardiology (R.F., A.W.d.H., M.G., B.J.M.M.), Radiology (M.G.), Clinical Epidemiology and Biostatistics (A.H.Z.), and Medical Biochemistry (V.d.W.), Academic Medical Center Amsterdam, Amsterdam; Interuniversity Cardiology Institute of the Netherlands, Utrecht (R.F., A.W.d.H., M.G., B.J.M.M.); Departments of Pathology (T.R.) and Clinical Genetics (D.M., A.M., F.S.v.D., H.E.M.-H., G.P.), VU University Medical Center, Amsterdam; Department of Cardiology, Radboud University Nijmegen Medical Center, Nijmegen (J.T.); Department of Cardiology, Leiden University Medical Center, Leiden (A.J.S.); and Department of Cardiology, University Medical Center Groningen, Groningen, the Netherlands (M.P.v.d.B.).

Background: It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups.

Methods And Results: In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197).

Conclusions: Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations.

Clinical Trial Registration: http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423.
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http://dx.doi.org/10.1161/CIRCGENETICS.114.000950DOI Listing
April 2015

PLS3 mutations in X-linked osteoporosis with fractures.

N Engl J Med 2013 Oct 2;369(16):1529-36. Epub 2013 Oct 2.

Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.

Plastin 3 (PLS3), a protein involved in the formation of filamentous actin (F-actin) bundles, appears to be important in human bone health, on the basis of pathogenic variants in PLS3 in five families with X-linked osteoporosis and osteoporotic fractures that we report here. The bone-regulatory properties of PLS3 were supported by in vivo analyses in zebrafish. Furthermore, in an additional five families (described in less detail) referred for diagnosis or ruling out of osteogenesis imperfecta type I, a rare variant (rs140121121) in PLS3 was found. This variant was also associated with a risk of fracture among elderly heterozygous women that was two times as high as that among noncarriers, which indicates that genetic variation in PLS3 is a novel etiologic factor involved in common, multi-factorial osteoporosis.
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http://dx.doi.org/10.1056/NEJMoa1308223DOI Listing
October 2013

Novel COL4A1 mutations cause cerebral small vessel disease by haploinsufficiency.

Hum Mol Genet 2013 Jan 12;22(2):391-7. Epub 2012 Oct 12.

Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium.

Mutations in COL4A1 have been identified in families with hereditary small vessel disease of the brain presumably due to a dominant-negative mechanism. Here, we report on two novel mutations in COL4A1 in two families with porencephaly, intracerebral hemorrhage and severe white matter disease caused by haploinsufficiency. Two families with various clinical presentations of cerebral microangiopathy and autosomal dominant inheritance were examined. Clinical, neuroradiological and genetic investigations were performed. Electron microscopy of the skin was also performed. In one of the families, sequence analysis revealed a one base deletion, c.2085del, leading to a frameshift and a premature stopcodon, p.(Gly696fs). In the other family, a splice site mutation was identified, c.2194-1G>A, which most likely leads to skipping of an exon with a frameshift and premature termination as a result. In fibroblasts of affected individuals from both the families, nonsense-mediated decay (NMD) of the mutant COL4A1 messenger RNAs (mRNAs) and a clear reduction of COL4A1 protein expression were demonstrated, indicating haploinsufficiency of COL4A1. Moreover, thickening of the capillary basement membrane in the skin was documented, similar to reports in patients with COL4A1 missense mutations. These findings suggest haploinsufficiency, a different mechanism from the commonly assumed dominant-negative effect, for COL4A1 mutations as a cause of (antenatal) intracerebral hemorrhage and white matter disease.
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http://dx.doi.org/10.1093/hmg/dds436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606013PMC
January 2013

Clinical utility gene card for: osteogenesis imperfecta.

Eur J Hum Genet 2013 Jun 26;21(6). Epub 2012 Sep 26.

Department of Clinical Genetics, Center for Connective Tissue Disorders, VU University Medical Center, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1038/ejhg.2012.210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3658202PMC
June 2013

Identification of a novel FBN1 gene mutation in a large Pakistani family with Marfan syndrome.

Mol Vis 2012 18;18:1918-26. Epub 2012 Jul 18.

Department of Biosciences, COMSATS Institute of Information Technology, Islamabad, Pakistan.

Purpose: To describe a novel mutation in the fibrillin-1 (FBN1) gene in a large Pakistani family with autosomal dominant Marfan syndrome (MFS).

Methods: Blood samples were collected of 11 family members affected with Marfan syndrome, and DNA was isolated by phenol-extraction. The coding exons of FBN1 were analyzed by polymerase chain reaction (PCR) and direct sequencing. One hundred-thirty controls were screened for a mutation in the FBN1 gene that was identified in this family by restriction fragment length polymorphism (RFLP) analysis.

Results: A novel heterozygous missense mutation c.2368T>A; p.Cys790Ser was observed in exon 19. This mutation substitutes a highly conserved cysteine residue by serine in a calcium binding epidermal growth factor-like domain (cbEGF) of FBN1. This mutation was present in all affected members and absent from unaffected individuals of the family in addition to 130 healthy Pakistani controls. Interestingly all affected family members presented with ectopia lentis, myopia and glaucoma, but lacked the cardinal cardiovascular features of MFS.

Conclusions: This is a first report of a mutation in FBN1 in MFS patients of Pakistani origin. The identification of a FBN1 mutation in this family confirms the diagnosis of MFS patients and expands the worldwide spectrum of FBN1 mutations.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413445PMC
December 2012

[Osteogenesis imperfecta: clinical and genetic heterogeneity].

Ned Tijdschr Geneeskd 2012 ;156(21):A4585

VU medisch centrum, afd. Klinische Genetica, Amsterdam.

Osteogenesis imperfecta is a hereditary connective tissue disorder characterized primarily by fractures with no or small causal antecedent; in most patients this is a consequence of diminished or abnormal production of collagen type I. It is a clinically heterogeneous disorder: it has been proposed recently to classify osteogenesis imperfecta in types I-V on the basis of the clinical picture and radiology. It is also a genetically heterogeneous disorder; 90% of cases are due to autosomal dominant mutations, while the remaining 10% are due to autosomal recessive mutations or of unknown cause. Osteogenesis imperfecta type I and to a lesser extent type IV are important differential diagnostic considerations in case of suspicion of non-accidental injury (NAI). When osteogenesis imperfecta is suspected, DNA analysis of the dominant COL1A1 and COL1A2 genes is currently the starting point for laboratory diagnosis unless there are strong indications for a recessive cause. Protein analysis based on skin biopsy remains indicated in specific cases.
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July 2012

EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta.

Eur J Hum Genet 2012 Jan 10;20(1):11-9. Epub 2011 Aug 10.

Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands.

Osteogenesis imperfecta (OI) comprises a group of inherited disorders characterized by bone fragility and increased susceptibility to fractures. Historically, the laboratory confirmation of the diagnosis OI rested on cultured dermal fibroblasts to identify decreased or abnormal production of abnormal type I (pro)collagen molecules, measured by gel electrophoresis. With the discovery of COL1A1 and COL1A2 gene variants as a cause of OI, sequence analysis of these genes was added to the diagnostic process. Nowadays, OI is known to be genetically heterogeneous. About 90% of individuals with OI are heterozygous for causative variants in the COL1A1 and COL1A2 genes. The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes. These advances in the molecular genetic diagnosis of OI prompted us to develop new guidelines for molecular testing and reporting of results in which we take into account that testing is also used to 'exclude' OI when there is suspicion of non-accidental injury. Diagnostic flow, methods and reporting scenarios were discussed during an international workshop with 17 clinicians and scientists from 11 countries and converged in these best practice guidelines for the laboratory diagnosis of OI.
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http://dx.doi.org/10.1038/ejhg.2011.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234509PMC
January 2012

Erosive vitreoretinopathy and wagner disease are caused by intronic mutations in CSPG2/Versican that result in an imbalance of splice variants.

Invest Ophthalmol Vis Sci 2006 Aug;47(8):3565-72

Department of Human Genetics, Radboud University Nijmegen Medical Centre, The Netherlands.

Purpose: Linkage intervals for erosive vitreoretinopathy (ERVR) and Wagner disease previously were found to overlap at 5q14.3. In a Japanese family with Wagner disease, a CSPG2/Versican splice site mutation (c.4004-2A-->G) was recently reported that resulted in a 39-nucleotide exon 8 in-frame deletion. We investigated whether CSPG2/Versican was mutated in six Dutch families and one Chinese family with Wagner disease and in a family with ERVR.

Methods: In all families, extensive ophthalmic examinations, haplotype analysis of the 5q14.3 region, and sequence analysis of CSPG2/Versican were performed. The effects of splice site mutations were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and real-time quantitative RT-PCR (QPCR).

Results: Three novel intron 7 sequence variants (c.4004-5T-->C, c.4004-5T-->A, c.4004-1G-->A) were identified in seven families. The c.4004-5T-->C variant was identified in four families with Wagner disease and a family with ERVR. The families were shown to carry the same 5q14.3 haplotype, strongly suggesting that this is a common Dutch founder variant. All three changes segregated with the disease in the respective families and were absent in 250 healthy individuals. In patients with the c.4004-5T-->A and c.4004-1G-->A variants, RT-PCR analysis of CSPG2/Versican showed activation of a cryptic splice site resulting in a 39-nt exon 8 in-frame deletion in splice variant V0. QPCR revealed a highly significant (P < 0.0001) and consistent increase of the V2 (>38-fold) and V3 (>12-fold) splice variants in all patients with intron 7 nucleotide changes and in a Chinese Wagner disease family, in which the genetic defect remains to be found.

Conclusions: Wagner disease and ERVR are allelic disorders. Seven of the eight families exhibit a variant in intron 7 of CSPG2/Versican. The conspicuous clustering of sequence variants in the splice acceptor site of intron 7 and the consistent upregulation of the V2 and V3 isoforms strongly suggest that Wagner disease and ERVR may belong to a largely overlooked group of diseases that are caused by mRNA isoform balance shifts, representing a novel disease mechanism.
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http://dx.doi.org/10.1167/iovs.06-0141DOI Listing
August 2006

The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene.

Graefes Arch Clin Exp Ophthalmol 2005 Feb 22;243(2):90-100. Epub 2004 Dec 22.

Department of Ophthalmology, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Background: The majority of studies on the retina-specific ATP-binding cassette transporter (ABCA4) gene have focussed on molecular genetic analysis; comparatively few studies have described the clinical aspects of ABCA4-associated retinal disorders. In this study, we demonstrate the spectrum of retinal dystrophies associated with ABCA4 gene mutations.

Methods: Nine well-documented patients representing distinct phenotypes in the continuum of ABCA4-related disorders were selected. All patients received an extensive ophthalmologic evaluation, including kinetic perimetry, fluorescein angiography, and electroretinography (ERG). Mutation analysis had been performed previously with the genotyping microarray (ABCR400 chip) and/or single-strand conformation polymorphism analysis in combination with direct DNA sequencing.

Results: In all patients, at least one pathologic ABCA4 mutation was identified. Patient 10034 represented the mild end of the phenotypic spectrum, demonstrating exudative age-related macular degeneration (AMD). Patient 24481 received the diagnosis of late-onset fundus flavimaculatus (FFM), patient 15168 demonstrated the typical FFM phenotype, and patient 19504 had autosomal recessive Stargardt disease (STGD1). Patients 11302 and 7608 exhibited progression from FFM/STGD1 to cone-rod dystrophy (CRD). A more typical CRD phenotype was found in patients 15680 and 12608. Finally, the most severe ABCA4-associated phenotype was retinitis pigmentosa (RP) in patient 11366. This phenotype was characterised by extensive atrophy with almost complete loss of peripheral and central retinal functions.

Conclusion: We describe nine patients during different stages of disease progression; together, these patients form a continuum of ABCA4-associated phenotypes. Besides characteristic disorders such as FFM/STGD1, CRD and RP, intermediate phenotypes may be encountered. Moreover, as the disease progresses, marked differences may be observed between initially comparable phenotypes. In contrast, distinctly different phenotypes may converge to a similar final stage, characterised by extensive chorioretinal atrophy and very low visual functions. The identified ABCA4 mutations in most, but not all, patients were compatible with the resulting phenotypes, as predicted by the genotype-phenotype model for ABCA4-associated disorders. With the advent of therapeutic options, recognition by the general ophthalmologist of the various retinal phenotypes associated with ABCA4 mutations is becoming increasingly important.
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http://dx.doi.org/10.1007/s00417-004-1079-4DOI Listing
February 2005

A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy.

Invest Ophthalmol Vis Sci 2004 Dec;45(12):4263-7

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Purpose: To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation.

Methods: Ophthalmic examination and mutation screening by direct sequencing of the ELOVL4 gene was performed in two affected individuals. Wild-type and mutant ELOVL4 genes were expressed as enhanced green fluorescent protein (EGFP) fusion proteins in transient transfection in NIH-3T3 and HEK293 cells. To determine the subcellular localization of ELOVL4, an endoplasmic-reticulum (ER)-specific marker for pDsRed2-ER was cotransfected with ELOVL4 constructs. Transfected cells were viewed by confocal microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody.

Results: Affected patients exhibited macular atrophy with surrounding flecks characteristic of adSTGD-like MD. A novel ELOVL4 p.Tyr270X mutation was detected in affected individuals. In cell-transfection studies, wild-type ELOVL4 localized preferentially to the ER. In contrast, the mutant protein appeared to be mislocalized within transfected cells.

Conclusions: In a European family with adSTGD-like MD, a novel ELOVL4 mutation was found to underlie the disorder. Transfection studies indicated that, unlike wild-type ELOVL4, the mutant protein does not localize to the ER but rather appears to be sequestered elsewhere in an aggregated pattern in the cytoplasm. Further analysis of the function of normal and mutant ELOVL4 will provide insight into the mechanism of macular degeneration.
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http://dx.doi.org/10.1167/iovs.04-0078DOI Listing
December 2004

Microarray-based mutation analysis of the ABCA4 (ABCR) gene in autosomal recessive cone-rod dystrophy and retinitis pigmentosa.

Eur J Hum Genet 2004 Dec;12(12):1024-32

Department of Ophthalmology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

Mutations in the ABCA4 gene have been associated with autosomal recessive Stargardt disease (STGD1), cone-rod dystrophy (CRD), and retinitis pigmentosa (RP). We employed a recently developed genotyping microarray, the ABCR400-chip, to search for known ABCA4 mutations in patients with isolated or autosomal recessive CRD (54 cases) or RP (90 cases). We performed detailed ophthalmologic examinations and identified at least one ABCA4 mutation in 18 patients (33%) with CRD and in five patients (5.6%) with RP. Single-strand conformation polymorphism (SSCP) analysis and subsequent DNA sequencing revealed four novel missense mutations (R24C, E161K, P597S, G618E) and a novel 1-bp deletion (5888delG). Ophthalmoscopic abnormalities in CRD patients ranged from minor granular pigmentary changes in the posterior pole to widespread atrophy. In 12 patients with recordable electroretinogram (ERG) tracings, a cone-rod pattern was detected. Three patients demonstrated progression from a retinal dystrophy resembling STGD1 to a more widespread degeneration, and were subsequently diagnosed as CRD. In addition to a variable degree of atrophy, all RP patients displayed ophthalmologic characteristics of classic RP. When detectable, ERG recordings in these patients demonstrated rod-cone patterns of photoreceptor degeneration. In conclusion, in this study, we show that the ABCA4 mutation chip is an efficient first screening tool for arCRD.
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http://dx.doi.org/10.1038/sj.ejhg.5201258DOI Listing
December 2004

Three families displaying the combination of Stargardt's disease with cone-rod dystrophy or retinitis pigmentosa.

Ophthalmology 2004 Mar;111(3):546-53

Department of Ophthalmology, University Medical Centre Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.

Objective: To investigate the clinical spectrum and molecular causes of retinal dystrophies in 3 families.

Design: Family molecular genetics study.

Participants: Sixteen patients and 15 relatives in 3 families.

Methods: Members of 3 families with multiple ABCA4-associated retinal disorders were clinically evaluated. Deoxyribonucleic acid samples of all affected individuals and their family members were analyzed for variants in all 50 exons of the ABCA4 gene.

Main Outcome Measures: ABCA4-associated retinal phenotypes and mutations in the ABCA4 gene.

Results: In family A, 2 sisters were diagnosed with Stargardt's disease (STGD); the eldest sister was compound heterozygous for the mild 2588G-->C and the severe 768G-->T mutation. Another patient in this family with a severe type of retinitis pigmentosa (RP) carried the 768G-->T mutation homozygously. In family B, 2 siblings presented with an RP of severity similar to that encountered in family A. Both were homozygous for the severe IVS33+1G-->A mutation. Two other family members with STGD were compound heterozygous for the 2588G-->C and IVS33+1G-->A mutations. In family C, all 5 siblings of generation II demonstrated age-related macular degeneration (AMD). In generations III and IV, 2 STGD patients and 1 cone-rod dystrophy (CRD) patient were present. In 1 STGD patient we identified a heterozygous 768G-->T mutation. Sequence analysis of the entire ABCA4 gene did not reveal the remaining 2 mutations. Nevertheless, the 2 patients with STGD, the patient with CRD, and 2 of the AMD patients shared a common haplotype spanning the ABCA4 gene.

Conclusions: Different mutations in the ABCA4 gene are the cause of STGD and RP or CRD in at least 2 and, possibly, 3 families. Patients with RP caused by ABCA4 mutations are characterized by an early onset and rapid progression of their retinal dystrophy, with extensive chorioretinal atrophy resulting in a very low visual acuity. Various combinations of relatively rare retinal disorders such as STGD, CRD, and RP in one family may not be as uncommon as once believed, in view of the relatively high carrier frequency of ABCA4 mutations (about 5%) in the general population.
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http://dx.doi.org/10.1016/j.ophtha.2003.06.010DOI Listing
March 2004

Autosomal dominant rhegmatogenous retinal detachment associated with an Arg453Ter mutation in the COL2A1 gene.

Invest Ophthalmol Vis Sci 2003 Sep;44(9):4035-43

Department of Ophthalmology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

Purpose: To investigate the clinical features and molecular causes of autosomal dominant rhegmatogenous retinal detachment (RRD) in two large families.

Methods: Clinical examination and linkage analysis of both families using markers flanking the COL2A1 gene associated with Stickler syndrome type 1, the loci for Wagner disease/erosive vitreoretinopathy (5q14.3), high myopia (18p11.31 and 12q21-q23), and nonsyndromic congenital retinal nonattachment (10q21).

Results: Fifteen individuals from family A and 12 individuals from family B showed RRD or retinal tears with minimal (family A) or no (family B) systemic characteristics of Stickler syndrome and no ocular features of Wagner disease or erosive vitreoretinopathy. The RRD cosegregated fully with a chromosomal region harboring the COL2A1 gene with maximum lod scores of 6.09 (family A) and 4.97 (family B). In family B, an Arg453Ter mutation was identified in exon 30 of the COL2A1 gene, that was previously described in a patient with classic Stickler syndrome. In family A, DNA sequence analysis revealed no mutation in the coding region and at the splice sites of the COL2A1 gene.

Conclusions: In two large families with RRD, linkage was found at the COL2A1 locus. In one of these families an Arg453Ter mutation was identified, which is surprising, because all predominantly ocular Stickler syndrome cases until now have been associated with protein-truncating mutations in exon 2, an exon subject to alternative splicing. In contrast, the Arg453Ter mutation and other protein-truncating mutations in the helical domain of COL2A1 have been associated until now with classic Stickler syndrome.
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http://dx.doi.org/10.1167/iovs.02-0736DOI Listing
September 2003

Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene.

Invest Ophthalmol Vis Sci 2002 Jun;43(6):1980-5

Department of Ophthalmology, University Medical Centre Nijmegen, Nijmegen, The Netherlands.

Purpose: To describe the phenotype of 12 patients with autosomal recessive or isolated cone-rod types of progressive retinal degeneration (CRD) caused by mutations in the ABCA4 gene.

Methods: The charts of patients who had originally received a diagnosis of isolated or autosomal recessive CRD were reviewed after molecular analysis revealed mutations in the ABCA4 gene.

Results: In two of the patients both the photopic and scotopic electroretinogram were nonrecordable. In the remainder, the photopic cone b-wave amplitudes appeared to be more seriously affected than the scotopic rod b-wave amplitudes. Although the clinical presentation was heterogeneous, all patients experienced visual loss early in life, impaired color vision, and a central scotoma. Fundoscopy revealed evidence of early-onset maculopathy, sometimes accompanied by involvement of the retinal periphery in the later stages of the disease.

Conclusions: Mutations in the ABCA4 gene are the pathologic cause of the CRD-like dystrophy in these patients, and the resultant clinical pictures are complex and heterogeneous. Given this wide clinical spectrum of CRD-like phenotypes associated with ABCA4 mutations, detailed clinical subclassifications are difficult and may not be very useful.
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June 2002

The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe.

Eur J Hum Genet 2002 Mar;10(3):197-203

Department of Human Genetics, University Medical Center Nijmegen, Nijmegen, The Netherlands.

Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G>C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G>C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G>C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G>C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G>C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.
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http://dx.doi.org/10.1038/sj.ejhg.5200784DOI Listing
March 2002