A Multi-Site Study of Constitutional Ring Chromosomes from 14 Cytogenetics Laboratories in the United States
Laboratory Genetics and Genomics
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Primary Categories:
- Laboratory Genetics
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Secondary Categories:
- Laboratory Genetics
Introduction:
Ring chromosomes (RCs) are intrachromosomal fusions associated with highly variable phenotypes. Constitutional RCs are identified by karyotype and are estimated to occur in ~1:50,000 live births. Static reports exist, with many lacking follow-ups and often initially described using only the karyotypic designations of the breakpoints. Multiple factors can influence the RC’s impact on the severity of the phenotype. An ascertainment bias towards the reporting of individuals more severely affected by RCs may also exist. Here, we present the clinical and cytogenomic findings part of a multisite study.
Methods:
To better understand the frequency of constitutional RCs, we conducted a retrospective, multi-center study analysis of the cytogenetic findings and associated phenotypes of de-identified individuals diagnosed with constitutional RCs. Multiple US Cytogenetics labs were invited to complete a brief Excel template to aid data curation of individuals with RCs. A review of postnatal individuals with available RC data from 14 US Cytogenetics laboratories was performed. We curated the clinical and cytogenetic laboratory testing information regarding 285 postnatal individuals with an RC.
Results:
A syndrome was suspected as the testing indication in multiple participants. Of the 286 RCs from 285 unique individuals submitted, 227 cases were pediatric, and 51 were adult-aged at ascertainment. An enrichment for acrocentric and gonosomal RCs was observed, which is consistent with existing literature. No RCs were identified for chromosomes 1, 11, 12, and 19. Single instances of RCs were observed for chromosomes 2, 3, 7, and 10. RC22 showed the highest frequency across the autosomes, with RCX showing the highest frequency of the gonosomes. Both mosaic and non-mosaic RCs are identified here. Excluding the gonosomal chromosomes, a near-equivalent number of males and females were identified. A subset had an RC that was familial in transmission, while only a subset was proven to be de novo in origin, which might reflect a lack of parental follow-up. The predominant specimen type studied was blood, likely due to ease of collection.
282 received confirmatory karyotype testing at least once. 117 had fluorescence in situ hybridization (FISH), 106 had chromosomal microarray results capable of clarifying breakpoints and identifying gene dosage imbalances, and 5 had other molecular studies. Importantly, 100 had a karyotype as the sole testing method, indicating these patients may benefit from genomic sizing and clarification of their breakpoints. One individual carried two ring chromosomes, likely arising from an XXY conceptus. Consistent with the literature, we also observed phenotypes ranging from sub/infertility to developmental and intellectual involvement, with dysmorphic features, depending on the chromosomes involved. At least two individuals came to attention due to an abnormal prenatal screening by cell-free DNA. This study added 238 novel cases and 48 previously published cases, as indicated by the submitting laboratories.
Conclusion:
This cohort provides potential aging-related data; notably, at least six have passed away. This data set also highlights the changes in methodologies in the cytogenomics field. As genome sequencing methods are implemented, this study should serve as a reminder to evaluate the possibility of structural rearrangements, like rings, especially when syndromic disorders are suspected. This study also illustrates the need for continued laboratory follow-up to improve genotype-phenotype correlations for patients with rare chromosomal abnormalities. In conclusion, conventional cytogenetics provides genomic context. We believe these cases contribute to the existing knowledge of structural rearrangements and can be used to provide new information to improve the care and management of patients affected by RCs.
Ring chromosomes (RCs) are intrachromosomal fusions associated with highly variable phenotypes. Constitutional RCs are identified by karyotype and are estimated to occur in ~1:50,000 live births. Static reports exist, with many lacking follow-ups and often initially described using only the karyotypic designations of the breakpoints. Multiple factors can influence the RC’s impact on the severity of the phenotype. An ascertainment bias towards the reporting of individuals more severely affected by RCs may also exist. Here, we present the clinical and cytogenomic findings part of a multisite study.
Methods:
To better understand the frequency of constitutional RCs, we conducted a retrospective, multi-center study analysis of the cytogenetic findings and associated phenotypes of de-identified individuals diagnosed with constitutional RCs. Multiple US Cytogenetics labs were invited to complete a brief Excel template to aid data curation of individuals with RCs. A review of postnatal individuals with available RC data from 14 US Cytogenetics laboratories was performed. We curated the clinical and cytogenetic laboratory testing information regarding 285 postnatal individuals with an RC.
Results:
A syndrome was suspected as the testing indication in multiple participants. Of the 286 RCs from 285 unique individuals submitted, 227 cases were pediatric, and 51 were adult-aged at ascertainment. An enrichment for acrocentric and gonosomal RCs was observed, which is consistent with existing literature. No RCs were identified for chromosomes 1, 11, 12, and 19. Single instances of RCs were observed for chromosomes 2, 3, 7, and 10. RC22 showed the highest frequency across the autosomes, with RCX showing the highest frequency of the gonosomes. Both mosaic and non-mosaic RCs are identified here. Excluding the gonosomal chromosomes, a near-equivalent number of males and females were identified. A subset had an RC that was familial in transmission, while only a subset was proven to be de novo in origin, which might reflect a lack of parental follow-up. The predominant specimen type studied was blood, likely due to ease of collection.
282 received confirmatory karyotype testing at least once. 117 had fluorescence in situ hybridization (FISH), 106 had chromosomal microarray results capable of clarifying breakpoints and identifying gene dosage imbalances, and 5 had other molecular studies. Importantly, 100 had a karyotype as the sole testing method, indicating these patients may benefit from genomic sizing and clarification of their breakpoints. One individual carried two ring chromosomes, likely arising from an XXY conceptus. Consistent with the literature, we also observed phenotypes ranging from sub/infertility to developmental and intellectual involvement, with dysmorphic features, depending on the chromosomes involved. At least two individuals came to attention due to an abnormal prenatal screening by cell-free DNA. This study added 238 novel cases and 48 previously published cases, as indicated by the submitting laboratories.
Conclusion:
This cohort provides potential aging-related data; notably, at least six have passed away. This data set also highlights the changes in methodologies in the cytogenomics field. As genome sequencing methods are implemented, this study should serve as a reminder to evaluate the possibility of structural rearrangements, like rings, especially when syndromic disorders are suspected. This study also illustrates the need for continued laboratory follow-up to improve genotype-phenotype correlations for patients with rare chromosomal abnormalities. In conclusion, conventional cytogenetics provides genomic context. We believe these cases contribute to the existing knowledge of structural rearrangements and can be used to provide new information to improve the care and management of patients affected by RCs.