IN THIS ISSUE OFFICIAL JOURNAL
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A Systematic Large-scale Phenotypic Analysis of de novo and Inherited Copy Number Variation Copy number variation (CNV) is a major cause of structural genome variation. By a common definition, a CNV represents a structural variant that may range in length from 1,000 to 5 million base pairs and most commonly involves the duplication or deletion of a genomic segment. The phenotypic abnormalities associated with pathogenic CNVs can be related to altered gene dosage. For example, supravalvular aortic stenosis occurs both with point mutations in the elastin gene as well as in Williams syndrome, a CNV disorder resulting from a heterozygous deletion of over 25 genes including the elastin gene. In other CNVs the pathomechanism may relate partly or entirely to the disruption of regulatory interactions, as has been demonstrated for a number of CNVs that lead to duplication or deletion of highly conserved tissue-specific enhancers. However, for many CNVs, next to nothing is known about the molecular etiology. In many cases the clinical interpretation of CNVs identified in patients referred for testing is quite challenging, since it can be impossible to confidently distinguish clinically relevant CNVs from rare neutral CNVs that can occur in the normal population.
The work of Vulto-van Silfhout and colleagues published in this issue (Hum Mutat 34: 1679–1687, 2013) is therefore important for a number of reasons. The authors performed a systematic clinical analysis of one of the largest datasets from a single center, comprising 5,531 carefully phenotyped patients referred for intellectual disability and/or multiple congenital anomalies. A total of 1,663 rare CNVs were identified in 1,388 of these patients. Patients with severe phenotypes were more likely to harbor de novo CNVs, whereas patients with a milder phenotype were enriched for both de novo and inherited CNVs, indicating that not only de novo but also inherited CNVs can be associated with a clinically relevant, albeit milder, phenotype. Moreover, patients with multiple rare CNVs tended to present with a more severe phenotype, supporting the concept that combinatorial effects of multiple CNVs may be present in some cases. A number of de novo CNVs were identified that contained only a single gene in patients with intellectual disability, thereby providing a list of good candidate genes for this phenotype.
Peter N. Robinson Institut f¨ur Medizinische Genetik und Humangenetik Charit´e – Universit¨atsmedizin Berlin, Germany DOI: 10.1002/humu.22200
C
2013 WILEY PERIODICALS, INC.
www.hgvs.org
A Systematic Large-scale Phenotypic Analysis of de novo and Inherited Copy Number Variation Copy number variation (CNV) is a major cause of structural genome variation. By a common definition, a CNV represents a structural variant that may range in length from 1,000 to 5 million base pairs and most commonly involves the duplication or deletion of a genomic segment. The phenotypic abnormalities associated with pathogenic CNVs can be related to altered gene dosage. For example, supravalvular aortic stenosis occurs both with point mutations in the elastin gene as well as in Williams syndrome, a CNV disorder resulting from a heterozygous deletion of over 25 genes including the elastin gene. In other CNVs the pathomechanism may relate partly or entirely to the disruption of regulatory interactions, as has been demonstrated for a number of CNVs that lead to duplication or deletion of highly conserved tissue-specific enhancers. However, for many CNVs, next to nothing is known about the molecular etiology. In many cases the clinical interpretation of CNVs identified in patients referred for testing is quite challenging, since it can be impossible to confidently distinguish clinically relevant CNVs from rare neutral CNVs that can occur in the normal population.
The work of Vulto-van Silfhout and colleagues published in this issue (Hum Mutat 34: 1679–1687, 2013) is therefore important for a number of reasons. The authors performed a systematic clinical analysis of one of the largest datasets from a single center, comprising 5,531 carefully phenotyped patients referred for intellectual disability and/or multiple congenital anomalies. A total of 1,663 rare CNVs were identified in 1,388 of these patients. Patients with severe phenotypes were more likely to harbor de novo CNVs, whereas patients with a milder phenotype were enriched for both de novo and inherited CNVs, indicating that not only de novo but also inherited CNVs can be associated with a clinically relevant, albeit milder, phenotype. Moreover, patients with multiple rare CNVs tended to present with a more severe phenotype, supporting the concept that combinatorial effects of multiple CNVs may be present in some cases. A number of de novo CNVs were identified that contained only a single gene in patients with intellectual disability, thereby providing a list of good candidate genes for this phenotype.
Peter N. Robinson Institut f¨ur Medizinische Genetik und Humangenetik Charit´e – Universit¨atsmedizin Berlin, Germany DOI: 10.1002/humu.22200
C
2013 WILEY PERIODICALS, INC.
