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1. Subtelomeric Rearrangements: Presentation of 21 Probands with Emphasis on Familial Cases

Author

Ana Rita Soares, Gabriela Soares, Manuela Mota-Freitas, Natália Oliva-Teles, and Ana Maria Fortuna

Subjects
Intellectual Disability/genetics, Subtelomeric Rearrangements Gene Rearrangement/genetics, Telomere/genetics, Medicine, Medicine (General), R5-920
Abstract

Introduction: Intellectual disability affects 2% – 3% of the general population, with a chromosomal abnormality being found in 4% – 28% of these patients and a cryptic subtelomeric abnormality in 3% – 16%. In most cases, these subtelomeric rearrangements are submicroscopic, requiring techniques other than conventional karyotype for detection. They may be de novo or inherited from an affected parent or from a healthy carrier of a balanced chromosomal abnormality. The aim of this study was to characterize patients from our medical genetics center, in whom both a deletion and duplication in subtelomeric regions were found. Material and Methods: Clinical and cytogenetic characterization of 21 probands followed at our center, from 1998 until 2017, with subtelomeric rearrangements. Results: There were 21 probands from 19 families presenting with intellectual disability and facial dysmorphisms. Seven had behavior changes, five had epilepsy and 14 presented with some other sign or symptom. Four had chromosomal abnormalities detected by conventional karyotype and four were diagnosed by array-comparative genomic hybridization. In four cases, parental studies were not possible. The online mendelian inheritance in man classification was provided whenever any of the phenotypes (deletion or duplication syndrome) was dominant. Discussion: Patients and relevant family members were clinically and cytogenetically characterized. Although rare, subtelomeric changes are a substantial cause of syndromic intellectual disability with important familial repercussions. It is essential to remember that a normal array-comparative genomic hybridization result does not exclude a balanced rearrangement in the parents. Conclusion: Parental genetic studies are essential not only for a complete characterization of the rearrangement, but also for accurate genetic counselling and screening of family members at risk for recurrence.

Published
2019
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2. Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach

Author

Carla Pinheiro, Rachael Catford, Patrícia Dias, Isabel Marques, Cheryl Shoubridge, Katherine B. Howell, Tessa Mattiske, Ana Berta Sousa, Ana Maria Fortuna, Marta Amado, Paula Jorge, Maria João Sá, Maria do Céu Mota, Richard J. Leventer, Angelina Calado, Lisa Aguiar, Gabriela Soares, Christina Soares, Rosário Santos, Rani Sachdev, Monique M. Ryan, and Kathryn Friend

Subjects
Genetics, business.industry, expanded polyalanine tract, Genetic counseling, Disease, Original Articles, medicine.disease, 3. Good health, Pathogenesis, pathogenic variant, Pathognomonic, intellectual disability, Intellectual disability, medicine, Homeobox, Human genome, ARX, business, Molecular Biology, Gene, Genetics (clinical), Aristaless-related homeobox gene
Abstract

The Aristaless-related homeobox (ARX) gene is implicated in intellectual disability with the most frequent pathogenic mutations leading to expansions of the first two polyalanine tracts. Here, we describe analysis of the ARX gene outlining the approaches in the Australian and Portuguese setting, using an integrated clinical and molecular strategy. We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non-pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX rarely cause intellectual disability. In addition, we identified five cases with a variant of unclear pathogenic significance. Owing to the inconsistent ARX variants description, publications were reviewed and ARX variant classifications were standardized and detailed unambiguously according to recommendations of the Human Genome Variation Society. In the absence of a pathognomonic clinical feature, we propose that molecular analysis of the ARX gene should be included in routine diagnostic practice in individuals with either nonsyndromic or syndromic intellectual disability. A definitive diagnosis of ARX-related disorders is crucial for an adequate clinical follow-up and accurate genetic counseling of at-risk family members. Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal was funded by FEDER funds of the Operational Program for Competitiveness Factors – COMPETE through FCT – Foundation for Science and Technology under the project: Fcomp-01-0124-FEDER-015896. The Neurogenetics research program in the Department of Paediatrics, University of Adelaide, Australia was funded by the Australian National Health and Medical Research Council (Grant No. 1063025). C. S. is supported Australian Research Council (Future Fellowship FT120100086)

Published
2015

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