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A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype

BACKGROUND: Genomic disorders present a wide spectrum of unrelated clinical entities that result from genomic rearrangements. Interstitial insertions requiring three points of breakage are rare genomic rearrangement events. The pseudoautosomal region PAR1, homologous between the Xp22 and Yp11 loci,...

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Autores principales: Si, Nuo, Meng, Xiaolu, Zhao, Zhen, Xia, Weibo, Zhang, Xue
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489244/
https://www.ncbi.nlm.nih.gov/pubmed/31036090
http://dx.doi.org/10.1186/s12967-019-1887-2
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author Si, Nuo
Meng, Xiaolu
Zhao, Zhen
Xia, Weibo
Zhang, Xue
author_facet Si, Nuo
Meng, Xiaolu
Zhao, Zhen
Xia, Weibo
Zhang, Xue
author_sort Si, Nuo
collection PubMed
description BACKGROUND: Genomic disorders present a wide spectrum of unrelated clinical entities that result from genomic rearrangements. Interstitial insertions requiring three points of breakage are rare genomic rearrangement events. The pseudoautosomal region PAR1, homologous between the Xp22 and Yp11 loci, has a high crossover and recombination rate. A 180 bp human-specific palindrome at Xq27.1 appears to be a hotspot for genomic rearrangement, and several genetic diseases/phenotypes associated with Xq27.1 palindrome-driven genomic rearrangement have been reported. Here we investigate a Chinese family with an extremely rare X-linked compound phenotype that remains undiagnosed. We attempt to identify underlying genetic causes by an integrated genome analysis. METHODS: A five-generation Chinese family with a distinct X-linked compound phenotype was recruited. Peripheral blood samples were collected and genomic DNA was extracted. Systemic physical and lab examinations were performed to evaluate the phenotype. An integrated genomic analysis was performed. Genotyping and linkage analysis were conducted to map the disease locus. Whole exome sequencing was performed to detect mutations in coding region. Whole genome sequencing was used to detect single nucleotide variations, small insertions, small deletions, or large structural variations. Copy number variation scanning was also performed on the genome scale. Interstitial insertion was confirmed by gap-PCR and quantitative-PCR, and breakpoint junctions were identified by genome walking and direct sequencing. Expression of products of genes nearby to the Xq27.1 palindrome was measured in peripheral blood from patients and unrelated controls via quantitative-PCR. RESULTS: The identified compound phenotype of genu varum, cubitus valgus, and everted lipsdoes not match any reported clinical entities. Fine mapping and linkage analysis identified a candidate interval of 4 Mb on the X chromosome. No potential coding region mutations were detected. A 105 kb genomic fragment of PAR1 containing no coding genes was duplicated and inserted into the center of a human-specific palindrome at Xq27.1. The interstitial insertion fully cosegregated with the family phenotype. No expression of FGF13 or SOX3 was detected in peripheral blood from the proband or unrelated controls. CONCLUSION: We report an extremely rare phenotype associated with an infrequently-seen genomic rearrangement. The novel compound phenotype is X-linked and characterized by genu varum, cubitus valgus, and everted lips. A 105 kb interstitial insertion of a PAR1 fragment into the Xq27.1 palindrome is associated with the phenotype in the family. The present study identified the underlying genetic cause of the phenotype, expanding the spectrum of known human-specific Xq27.1 palindrome insertion events and associated phenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-019-1887-2) contains supplementary material, which is available to authorized users.
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spelling pubmed-64892442019-06-05 A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype Si, Nuo Meng, Xiaolu Zhao, Zhen Xia, Weibo Zhang, Xue J Transl Med Research BACKGROUND: Genomic disorders present a wide spectrum of unrelated clinical entities that result from genomic rearrangements. Interstitial insertions requiring three points of breakage are rare genomic rearrangement events. The pseudoautosomal region PAR1, homologous between the Xp22 and Yp11 loci, has a high crossover and recombination rate. A 180 bp human-specific palindrome at Xq27.1 appears to be a hotspot for genomic rearrangement, and several genetic diseases/phenotypes associated with Xq27.1 palindrome-driven genomic rearrangement have been reported. Here we investigate a Chinese family with an extremely rare X-linked compound phenotype that remains undiagnosed. We attempt to identify underlying genetic causes by an integrated genome analysis. METHODS: A five-generation Chinese family with a distinct X-linked compound phenotype was recruited. Peripheral blood samples were collected and genomic DNA was extracted. Systemic physical and lab examinations were performed to evaluate the phenotype. An integrated genomic analysis was performed. Genotyping and linkage analysis were conducted to map the disease locus. Whole exome sequencing was performed to detect mutations in coding region. Whole genome sequencing was used to detect single nucleotide variations, small insertions, small deletions, or large structural variations. Copy number variation scanning was also performed on the genome scale. Interstitial insertion was confirmed by gap-PCR and quantitative-PCR, and breakpoint junctions were identified by genome walking and direct sequencing. Expression of products of genes nearby to the Xq27.1 palindrome was measured in peripheral blood from patients and unrelated controls via quantitative-PCR. RESULTS: The identified compound phenotype of genu varum, cubitus valgus, and everted lipsdoes not match any reported clinical entities. Fine mapping and linkage analysis identified a candidate interval of 4 Mb on the X chromosome. No potential coding region mutations were detected. A 105 kb genomic fragment of PAR1 containing no coding genes was duplicated and inserted into the center of a human-specific palindrome at Xq27.1. The interstitial insertion fully cosegregated with the family phenotype. No expression of FGF13 or SOX3 was detected in peripheral blood from the proband or unrelated controls. CONCLUSION: We report an extremely rare phenotype associated with an infrequently-seen genomic rearrangement. The novel compound phenotype is X-linked and characterized by genu varum, cubitus valgus, and everted lips. A 105 kb interstitial insertion of a PAR1 fragment into the Xq27.1 palindrome is associated with the phenotype in the family. The present study identified the underlying genetic cause of the phenotype, expanding the spectrum of known human-specific Xq27.1 palindrome insertion events and associated phenotypes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12967-019-1887-2) contains supplementary material, which is available to authorized users. BioMed Central 2019-04-29 /pmc/articles/PMC6489244/ /pubmed/31036090 http://dx.doi.org/10.1186/s12967-019-1887-2 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Si, Nuo
Meng, Xiaolu
Zhao, Zhen
Xia, Weibo
Zhang, Xue
A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title_full A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title_fullStr A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title_full_unstemmed A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title_short A 105 kb interstitial insertion in the Xq27.1 palindrome from pseudoautosomal region PAR1 causes a novel X-linked recessive compound phenotype
title_sort 105 kb interstitial insertion in the xq27.1 palindrome from pseudoautosomal region par1 causes a novel x-linked recessive compound phenotype
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489244/
https://www.ncbi.nlm.nih.gov/pubmed/31036090
http://dx.doi.org/10.1186/s12967-019-1887-2
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