Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof-of-concept examples
| Autor: | Cecilia Mancini, Elena Gaidolfi, Cristina Molinatto, Elisa Biamino, Marco Tartaglia, Andrea Ciolfi, Eleonora Di Gregorio, Elisa Giorgio, Simona Cavalieri, Viviana Caputo, Alessandro Bruselles, Alfredo Brusco, Margherita Silengo, Elga Fabia Belligni, Alessandro Calcia, Giovanni Battista Ferrero |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Proband Microcephaly Ataxia Cerebellar Ataxia Developmental Disabilities de novo CNV intellectual disability TRAPPC9 VLDRL whole exome sequencing Genetics Genetics (clinical) Biology Nervous System Malformations Bioinformatics 03 medical and health sciences Cerebellum medicine Humans Exome Genetic Predisposition to Disease Child Cerebellar hypoplasia Exome sequencing Comparative Genomic Hybridization Cerebellar ataxia medicine.disease Hypotonia Pedigree Phenotype 030104 developmental biology Receptors LDL Child Preschool Mutation Intercellular Signaling Peptides and Proteins Female medicine.symptom Carrier Proteins |
| Zdroj: | American Journal of Medical Genetics Part A. 170:1772-1779 |
| ISSN: | 1552-4825 |
| Popis: | Whole exome sequencing (WES) is a powerful tool to identify clinically undefined forms of intellectual disability/developmental delay (ID/DD), especially in consanguineous families. Here we report the genetic definition of two sporadic cases, with syndromic ID/DD for whom array-Comparative Genomic Hybridization (aCGH) identified a de novo copy number variant (CNV) of uncertain significance. The phenotypes included microcephaly with brachycephaly and a distinctive facies in one proband, and hypotonia in the legs and mild ataxia in the other. WES allowed identification of a functionally relevant homozygous variant affecting a known disease gene for rare syndromic ID/DD in each proband, that is, c.1423C>T (p.Arg377*) in the Trafficking Protein Particle Complex 9 (TRAPPC9), and c.154T>C (p.Cys52Arg) in the Very Low Density Lipoprotein Receptor (VLDLR). Four mutations affecting TRAPPC9 have been previously reported, and the present finding further depicts this syndromic form of ID, which includes microcephaly with brachycephaly, corpus callosum hypoplasia, facial dysmorphism, and overweight. VLDLR-associated cerebellar hypoplasia (VLDLR-CH) is characterized by non-progressive congenital ataxia and moderate-to-profound intellectual disability. The c.154T>C (p.Cys52Arg) mutation was associated with a very mild form of ataxia, mild intellectual disability, and cerebellar hypoplasia without cortical gyri simplification. In conclusion, we report two novel cases with rare causes of autosomal recessive ID, which document how interpreting de novo array-CGH variants represents a challenge in consanguineous families; as such, clinical WES should be considered in diagnostic testing. © 2016 Wiley Periodicals, Inc. |
| Databáze: | OpenAIRE |
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