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Molecular diagnosis and novel genes and phenotypes in a pediatric thoracic insufficiency cohort

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 wh...

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Detalles Bibliográficos
Autores principales: Strong, Alanna, Behr, Meckenzie, Lott, Carina, Clark, Abigail J., Mentch, Frank, Da Silva, Renata Pellegrino, Rux, Danielle R., Campbell, Robert, Skraban, Cara, Wang, Xiang, Anari, Jason B., Sinder, Benjamin, Cahill, Patrick J., Sleiman, Patrick, Hakonarson, Hakon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9849333/
https://www.ncbi.nlm.nih.gov/pubmed/36653407
http://dx.doi.org/10.1038/s41598-023-27641-0
Descripción
Sumario: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.