Dataset Information

High incidence of recurrent copy number variants in patients with isolated and syndromic Mullerian aplasia.

ABSTRACT: BACKGROUND:Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at different genomic loci. METHODS:In order to obtain an overview of the contribution of copy number variation to both isolated and syndromic forms of Müllerian aplasia, copy number assays were performed in a series of 63 cases, of which 25 were syndromic and 38 isolated. RESULTS:A high incidence (9/63, 14%) of recurrent copy number variants in this cohort is reported here. These comprised four cases of microdeletion at 16p11.2, an autism susceptibility locus not previously associated with Müllerian aplasia, four cases of microdeletion at 17q12, and one case of a distal 22q11.2 microdeletion. Microdeletions at 16p11.2 and 17q12 were found in 4/38 (10.5%) cases with isolated Müllerian aplasia, and at 16p11.2, 17q12 and 22q11.2 (distal) in 5/25 cases (20%) with syndromic Müllerian aplasia. CONCLUSION:The finding of microdeletion at 16p11.2 in 2/38 (5%) of isolated and 2/25 (8%) of syndromic cases suggests a significant contribution of this copy number variant alone to the pathogenesis of Müllerian aplasia. Overall, the high incidence of recurrent copy number variants in all forms of Müllerian aplasia has implications for the understanding of the aetiopathogenesis of the condition, and for genetic counselling in families affected by it.

SUBMITTER: Nik-Zainal S

PROVIDER: S-EPMC3322361 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia.

Nik-Zainal Serena S Strick Reiner R Storer Mekayla M Huang Ni N Rad Roland R Willatt Lionel L Fitzgerald Tomas T Martin Vicki V Sandford Richard R Carter Nigel P NP Janecke Andreas R AR Renner Stefan P SP Oppelt Patricia G PG Oppelt Peter P Schulze Christine C Brucker Sara S Hurles Matthew M Beckmann Matthias W MW Strissel Pamela L PL Shaw-Smith Charles C

Journal of medical genetics 20110128 3

<h4>Background</h4>Congenital malformations involving the Müllerian ducts are observed in around 5% of infertile women. Complete aplasia of the uterus, cervix, and upper vagina, also termed Müllerian aplasia or Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, occurs with an incidence of around 1 in 4500 female births, and occurs in both isolated and syndromic forms. Previous reports have suggested that a proportion of cases, especially syndromic cases, are caused by variation in copy number at di ...[more]

PMID: 21278390

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Project description:BACKGROUND: Algorithms and software for CNV detection have been developed, but they detect the CNV regions sample-by-sample with individual-specific breakpoints, while common CNV regions are likely to occur at the same genomic locations across different individuals in a homogenous population. Current algorithms to detect common CNV regions do not account for the varying reliability of the individual CNVs, typically reported as confidence scores by SNP-based CNV detection algorithms. General methodologies for identifying these recurrent regions, especially those directed at SNP arrays, are still needed. RESULTS: In this paper, we describe two new approaches for identifying common CNV regions based on (i) the frequency of occurrence of reliable CNVs, where reliability is determined by high confidence scores, and (ii) a weighted frequency of occurrence of CNVs, where the weights are determined by the confidence scores. In addition, motivated by the fact that we often observe partially overlapping CNV regions as a mixture of two or more distinct subregions, regions identified using the two approaches can be fine-tuned to smaller sub-regions using a clustering algorithm. We compared the performance of the methods with sequencing-based results in terms of discordance rates, rates of departure from Hardy-Weinberg equilibrium (HWE) and average frequency and size of the identified regions. The discordance rates as well as the rates of departure from HWE decrease when we select CNVs with higher confidence scores. We also performed comparisons with two previously published methods, STAC and GISTIC, and showed that the methods we consider are better at identifying low-frequency but high-confidence CNV regions. CONCLUSIONS: The proposed methods for identifying common CNV regions in multiple individuals perform well compared to existing methods. The identified common regions can be used for downstream analyses such as group comparisons in association studies.

Dataset Information

High incidence of recurrent copy number variants in patients with isolated and syndromic Mullerian aplasia.

Publications

High incidence of recurrent copy number variants in patients with isolated and syndromic Müllerian aplasia.

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