Cargando…
Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip
BACKGROUND: Developmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle r...
Autores principales: | , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361705/ https://www.ncbi.nlm.nih.gov/pubmed/28327142 http://dx.doi.org/10.1186/s12881-017-0393-8 |
_version_ | 1782516818350440448 |
---|---|
author | Basit, Sulman Albalawi, Alia M. Alharby, Essa Khoshhal, Khalid I. |
author_facet | Basit, Sulman Albalawi, Alia M. Alharby, Essa Khoshhal, Khalid I. |
author_sort | Basit, Sulman |
collection | PubMed |
description | BACKGROUND: Developmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle radiographic signs through mild instability to frank dislocations with acetabular dysplasia. A Saudi family with three affected individuals with DDH was identified and genetic analysis was performed to detect the possible genetic defect(s) underlying DDH in the affected members of the family. METHODS: We performed whole genome genotyping using Illumina HumanOmni 2.5 M array and whole exome sequencing (WES) using Nextera Rapid capture kit and Illumina NextSeq500 instrument in four individuals of a family with DDH. RESULTS: SNP data analysis did not identify any runs of homozygosity and copy number variations. Identity-by-descent (IBD) analysis on whole genome genotyping data identified a shared haplotypes on chromosome 1 in affected individuals. An analysis of the WES data identified rare heterozygous variants in HSPG2 and ATP2B4 genes in the affected individuals. Multiple prediction software predicted that the variants identified are damaging. Moreover, in silico analysis showed that HSPG2 regulates ATP2B4 expression using a variety of transcription factors. CONCLUSION: Our results indicate that there might be a functional epistatic interaction between HSPG2 and ATP2B4, and DDH in the family studied is due to a combined effect of both variants. These variants are also present in the asymptomatic mother suggesting that the variants in HSPG2 and ATP2B4 are incompletely penetrant. This study provides the first evidence of digenic inheritance of DDH in a family and extends the spectrum of genetic heterogeneity in this human disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-017-0393-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5361705 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-53617052017-03-24 Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip Basit, Sulman Albalawi, Alia M. Alharby, Essa Khoshhal, Khalid I. BMC Med Genet Research Article BACKGROUND: Developmental dysplasia of the hip (DDH) is a common pathological condition of the musculoskeletal system in infants which results in a congenital and developmental malformation of the hip joint. DDH is a spectrum of pathologies affecting the infant hip ranging from asymptomatic subtle radiographic signs through mild instability to frank dislocations with acetabular dysplasia. A Saudi family with three affected individuals with DDH was identified and genetic analysis was performed to detect the possible genetic defect(s) underlying DDH in the affected members of the family. METHODS: We performed whole genome genotyping using Illumina HumanOmni 2.5 M array and whole exome sequencing (WES) using Nextera Rapid capture kit and Illumina NextSeq500 instrument in four individuals of a family with DDH. RESULTS: SNP data analysis did not identify any runs of homozygosity and copy number variations. Identity-by-descent (IBD) analysis on whole genome genotyping data identified a shared haplotypes on chromosome 1 in affected individuals. An analysis of the WES data identified rare heterozygous variants in HSPG2 and ATP2B4 genes in the affected individuals. Multiple prediction software predicted that the variants identified are damaging. Moreover, in silico analysis showed that HSPG2 regulates ATP2B4 expression using a variety of transcription factors. CONCLUSION: Our results indicate that there might be a functional epistatic interaction between HSPG2 and ATP2B4, and DDH in the family studied is due to a combined effect of both variants. These variants are also present in the asymptomatic mother suggesting that the variants in HSPG2 and ATP2B4 are incompletely penetrant. This study provides the first evidence of digenic inheritance of DDH in a family and extends the spectrum of genetic heterogeneity in this human disorder. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12881-017-0393-8) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-21 /pmc/articles/PMC5361705/ /pubmed/28327142 http://dx.doi.org/10.1186/s12881-017-0393-8 Text en © The Author(s). 2017 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 Article Basit, Sulman Albalawi, Alia M. Alharby, Essa Khoshhal, Khalid I. Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title | Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title_full | Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title_fullStr | Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title_full_unstemmed | Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title_short | Exome sequencing identified rare variants in genes HSPG2 and ATP2B4 in a family segregating developmental dysplasia of the hip |
title_sort | exome sequencing identified rare variants in genes hspg2 and atp2b4 in a family segregating developmental dysplasia of the hip |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361705/ https://www.ncbi.nlm.nih.gov/pubmed/28327142 http://dx.doi.org/10.1186/s12881-017-0393-8 |
work_keys_str_mv | AT basitsulman exomesequencingidentifiedrarevariantsingeneshspg2andatp2b4inafamilysegregatingdevelopmentaldysplasiaofthehip AT albalawialiam exomesequencingidentifiedrarevariantsingeneshspg2andatp2b4inafamilysegregatingdevelopmentaldysplasiaofthehip AT alharbyessa exomesequencingidentifiedrarevariantsingeneshspg2andatp2b4inafamilysegregatingdevelopmentaldysplasiaofthehip AT khoshhalkhalidi exomesequencingidentifiedrarevariantsingeneshspg2andatp2b4inafamilysegregatingdevelopmentaldysplasiaofthehip |