Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof‐of‐concept examples
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Whole exome sequencing is necessary to clarify ID/DD cases with de novo copy number variants of uncertain significance: Two proof‐of‐concept examples
- Date Crossref
- 25/04/2016
- Éditeur
- Wiley
- Type
- journal-article
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Department of Medical Sciences pays non établi dans la noticeStructure de recherche
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University of Turin pays non établi dans la noticeUniversité ou école supérieure
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Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione pays non établi dans la noticeStructure de recherche
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Bambino Gesù Children's Hospital pays non établi dans la noticeÉtablissement de santé
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Sapienza University of Rome Department of Experimental Medicine pays non établi dans la noticeUniversité ou école supérieure
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Centro Diagnostico Italiano pays non établi dans la noticeÉtablissement de santé
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Istituto Superiore di Sanità pays non établi dans la noticeOrganisme public
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University of Torino Department of Medical Sciences pays non établi dans la noticeUniversité ou école supérieure
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Centro di Ricerca per gli alimenti e la nutrizione CREA Rome Italy pays non établi dans la noticeInstitution
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Genetics and Rare Diseases Research Division Ospedale Pediatrico Bambino Gesù IRCSS Rome Italy pays non établi dans la noticeInstitution
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Città della Salute e della Scienza University Hospital Medical Genetics Unit Turin Italy pays non établi dans la noticeUniversité ou école supérieure
Department of Medical Sciences, University of Turin et Istituto Nazionale di Ricerca per gli Alimenti e la Nutrizione, avec 9 autres affiliations.
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