Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort
Abstract Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We per...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-27641-0 |
| _version_ | 1797945958663716864 |
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| author | Alanna Strong Meckenzie Behr Carina Lott Abigail J. Clark Frank Mentch Renata Pellegrino Da Silva Danielle R. Rux Robert Campbell Cara Skraban Xiang Wang Jason B. Anari Benjamin Sinder Patrick J. Cahill Patrick Sleiman Hakon Hakonarson |
| author_facet | Alanna Strong Meckenzie Behr Carina Lott Abigail J. Clark Frank Mentch Renata Pellegrino Da Silva Danielle R. Rux Robert Campbell Cara Skraban Xiang Wang Jason B. Anari Benjamin Sinder Patrick J. Cahill Patrick Sleiman Hakon Hakonarson |
| author_sort | Alanna Strong |
| collection | DOAJ |
| description | Abstract Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We performed whole exome sequencing on a cohort of 42 children with thoracic insufficiency to elucidate the underlying molecular etiologies of syndromic and non-syndromic thoracic insufficiency and predict extra-skeletal manifestations and disease progression. Molecular diagnosis was established in 24/42 probands (57%), with 18/24 (75%) probands having definitive diagnoses as defined by laboratory and clinical criteria and 6/24 (25%) probands having strong candidate genes. Gene identified in cohort patients most commonly encoded components of the primary cilium, connective tissue, and extracellular matrix. A novel association between KIF7 and USP9X variants and thoracic insufficiency was identified. We report and expand the genetic and phenotypic spectrum of a cohort of children with thoracic insufficiency, reinforce the prevalence of extra-skeletal manifestations in thoracic insufficiency syndromes, and expand the phenotype of KIF7 and USP9X-related disease to include thoracic insufficiency. |
| first_indexed | 2024-04-10T21:03:16Z |
| format | Article |
| id | doaj.art-822bda9121314ca48efff01330f63e08 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-10T21:03:16Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-822bda9121314ca48efff01330f63e082023-01-22T12:12:30ZengNature PortfolioScientific Reports2045-23222023-01-0113111010.1038/s41598-023-27641-0Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohortAlanna Strong0Meckenzie Behr1Carina Lott2Abigail J. Clark3Frank Mentch4Renata Pellegrino Da Silva5Danielle R. Rux6Robert Campbell7Cara Skraban8Xiang Wang9Jason B. Anari10Benjamin Sinder11Patrick J. Cahill12Patrick Sleiman13Hakon Hakonarson14Division of Human Genetics, Children’s Hospital of PhiladelphiaThe Center for Applied Genomics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaThe Center for Applied Genomics, Children’s Hospital of PhiladelphiaDivision of Human Genetics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Human Genetics, Children’s Hospital of PhiladelphiaThe Center for Applied Genomics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Orthopedics, Children’s Hospital of PhiladelphiaDivision of Human Genetics, Children’s Hospital of PhiladelphiaDivision of Human Genetics, Children’s Hospital of PhiladelphiaAbstract Thoracic insufficiency syndromes are a genetically and phenotypically heterogeneous group of disorders characterized by congenital abnormalities or progressive deformation of the chest wall and/or vertebrae that result in restrictive lung disease and compromised respiratory capacity. We performed whole exome sequencing on a cohort of 42 children with thoracic insufficiency to elucidate the underlying molecular etiologies of syndromic and non-syndromic thoracic insufficiency and predict extra-skeletal manifestations and disease progression. Molecular diagnosis was established in 24/42 probands (57%), with 18/24 (75%) probands having definitive diagnoses as defined by laboratory and clinical criteria and 6/24 (25%) probands having strong candidate genes. Gene identified in cohort patients most commonly encoded components of the primary cilium, connective tissue, and extracellular matrix. A novel association between KIF7 and USP9X variants and thoracic insufficiency was identified. We report and expand the genetic and phenotypic spectrum of a cohort of children with thoracic insufficiency, reinforce the prevalence of extra-skeletal manifestations in thoracic insufficiency syndromes, and expand the phenotype of KIF7 and USP9X-related disease to include thoracic insufficiency.https://doi.org/10.1038/s41598-023-27641-0 |
| spellingShingle | Alanna Strong Meckenzie Behr Carina Lott Abigail J. Clark Frank Mentch Renata Pellegrino Da Silva Danielle R. Rux Robert Campbell Cara Skraban Xiang Wang Jason B. Anari Benjamin Sinder Patrick J. Cahill Patrick Sleiman Hakon Hakonarson Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort Scientific Reports |
| title | Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| title_full | Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| title_fullStr | Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| title_full_unstemmed | Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| title_short | Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| title_sort | molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort |
| url | https://doi.org/10.1038/s41598-023-27641-0 |
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