Publications by authors named "Ilse Meerschaut"

5 Publications

  • Page 1 of 1

Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum.

Am J Med Genet A 2019 12 9;179(12):2494-2499. Epub 2019 Oct 9.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

Myhre syndrome is a rare multisystem connective tissue disorder, characterized by short stature, facial dysmorphology, variable intellectual disability, skeletal abnormalities, arthropathy, cardiopathy, laryngotracheal anomalies, and stiff skin. So far, all molecularly confirmed cases harbored a de novo heterozygous gain-of-function mutation in SMAD4, encoding the SMAD4 transducer protein required for both transforming growth factor-beta and bone morphogenic proteins signaling. We report on four novel patients (one female proband and her two affected children, and one male proband) with Myhre syndrome harboring the recurrent c.1486C>T (p.Arg496Cys) mutation in SMAD4. The female proband presented with a congenital heart defect, vertebral anomalies, and facial dysmorphic features. She developed severe tracheal stenosis requiring a total laryngectomy. With assisted reproductive treatment, she gave birth to two affected children. The second proband presented with visual impairment following lensectomy in childhood, short stature, brachydactyly, stiff skin, and decreased peripheral sensitivity. Transmission electron microscopy (TEM) of the dermis shows irregular elastin cores with globular deposits and almost absent surrounding microfibrils and suggests age-related increased collagen deposition. We report on the first familial case of Myhre syndrome and illustrate the variable clinical spectrum of the disorder. Despite the primarily fibrotic nature of the disease, TEM analysis mainly indicates elastic fiber anomalies.
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http://dx.doi.org/10.1002/ajmg.a.61377DOI Listing
December 2019

A clinical scoring system for congenital contractural arachnodactyly.

Genet Med 2020 01 18;22(1):124-131. Epub 2019 Jul 18.

Center for Human Genetics, Institute of Pathology and Genetics (IPG), Gosselies, Belgium.

Purpose: Congenital contractural arachnodactyly (CCA) is an autosomal dominant connective tissue disorder manifesting joint contractures, arachnodactyly, crumpled ears, and kyphoscoliosis as main features. Due to its rarity, rather aspecific clinical presentation, and overlap with other conditions including Marfan syndrome, the diagnosis is challenging, but important for prognosis and clinical management. CCA is caused by pathogenic variants in FBN2, encoding fibrillin-2, but locus heterogeneity has been suggested. We designed a clinical scoring system and diagnostic criteria to support the diagnostic process and guide molecular genetic testing.

Methods: In this retrospective study, we assessed 167 probands referred for FBN2 analysis and classified them into a FBN2-positive (n = 44) and FBN2-negative group (n = 123) following molecular analysis. We developed a 20-point weighted clinical scoring system based on the prevalence of ten main clinical characteristics of CCA in both groups.

Results: The total score was significantly different between the groups (P < 0.001) and was indicative for classifying patients into unlikely CCA (total score <7) and likely CCA (total score ≥7) groups.

Conclusions: Our clinical score is helpful for clinical guidance for patients suspected to have CCA, and provides a quantitative tool for phenotyping in research settings.
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http://dx.doi.org/10.1038/s41436-019-0609-8DOI Listing
January 2020

Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines for the Interpretation of Sequenced Variants in the Gene for Marfan Syndrome: Proposal for a Disease- and Gene-Specific Guideline.

Circ Genom Precis Med 2018 06;11(6):e002039

Center for Medical Genetics (L.M.-M., F.S., I.M., A.D.P., W.S., S.S., P.C., B.C., M.R., J.D.B.).

Background: The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology proposed new variant interpretation guidelines. Gene-specific characteristics were, however, not considered, sometimes leading to inconsistent variant interpretation.

Methods: To allow a more uniform interpretation of variants in the (fibrillin-1) gene, causing Marfan syndrome, we tailored these guidelines to this gene and disease. We adapted 15 of the 28 general criteria and classified 713 variants previously identified in our laboratory as causal mutation or variant of uncertain significance according to these adapted guidelines. We then compared the agreement between previous methods and the adapted American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria.

Results: Agreement between the methods was 86.4% (K-alpha, 0.6). Application of the tailored guidelines resulted in an increased number of variants of uncertain significance (14.5% to 24.2%). Of the 85 variants that were downscaled to likely benign or variant of uncertain significance, 59.7% were missense variants outside a well-established functional site. Available clinical- or segregation data, necessary to further classify these types of variants, were in many cases insufficient to aid the classification.

Conclusions: Our study shows that classification of variants remains challenging and may change over time. Currently, a higher level of evidence is necessary to classify a variant as pathogenic. Gene-specific guidelines may be useful to allow a more precise and uniform interpretation of the variants to accurately support clinical decision-making.
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http://dx.doi.org/10.1161/CIRCGEN.117.002039DOI Listing
June 2018

-related intellectual disability syndrome: a recognisable entity.

J Med Genet 2017 09 22;54(9):613-623. Epub 2017 Jul 22.

Laboratory of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Mutations in forkhead box protein P1 () cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far.

Methods: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting.

Results: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability.

Conclusions: -related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.
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http://dx.doi.org/10.1136/jmedgenet-2017-104579DOI Listing
September 2017

Severe congenital neutropenia with neurological impairment due to a homozygous VPS45 p.E238K mutation: A case report suggesting a genotype-phenotype correlation.

Am J Med Genet A 2015 Dec 11;167A(12):3214-8. Epub 2015 Sep 11.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

VPS45 mutations cause severe congenital neutropenia (SCN). We report on a girl with SCN and neurological impairment harboring a homozygous p.E238K mutation in VPS45 (vacuolar sorting protein 45). She successfully underwent hematopoietic stem cell transplantation. Our findings delineate the phenotype and indicate a possible genotype-phenotype correlation for neurological involvement.
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http://dx.doi.org/10.1002/ajmg.a.37367DOI Listing
December 2015