TY - JOUR
T1 - Clinical utility of comprehensive gene panel testing for common and rare causes of skeletal dysplasia and other skeletal disorders
T2 - Results from the largest cohort to date
AU - MacCarrick, Gretchen
AU - Aradhya, Swaroop
AU - Bailey, Mitch
AU - Chu, Dorna
AU - Hunt, Abigail
AU - Izzo, Emanuela
AU - Krakow, Deborah
AU - Mackenzie, William
AU - Poll, Sarah
AU - Raggio, Cathleen
AU - Shediac, Renée
AU - White, Klane K.
AU - McLaughlin, Heather M.
AU - Seratti, Guillermo
N1 - Publisher Copyright:
© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
PY - 2024/9
Y1 - 2024/9
N2 - Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019–April 2022). Median (range) age was 8 (0–90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.
AB - Molecular genetics enables more precise diagnoses of skeletal dysplasia and other skeletal disorders (SDs). We investigated the clinical utility of multigene panel testing for 5011 unrelated individuals with SD in the United States (December 2019–April 2022). Median (range) age was 8 (0–90) years, 70.5% had short stature and/or disproportionate growth, 27.4% had a positive molecular diagnosis (MDx), and 30 individuals received two MDx. Genes most commonly contributing to MDx were FGFR3 (16.9%), ALPL (13.0%), and COL1A1 (10.3%). Most of the 112 genes associated with ≥1 MDx were primarily involved in signal transduction (n = 35), metabolism (n = 23), or extracellular matrix organization (n = 17). There were implications associated with specific care/treatment options for 84.4% (1158/1372) of MDx-positive individuals; >50% were linked to conditions with targeted therapy approved or in clinical development, including osteogenesis imperfecta, achondroplasia, hypophosphatasia, and mucopolysaccharidosis. Forty individuals with initially inconclusive results became MDx-positive following family testing. Follow-up mucopolysaccharidosis enzyme activity testing was positive in 14 individuals (10 of these were not MDx-positive). Our findings showed that inclusion of metabolic genes associated with SD increased the clinical utility of a gene panel and confirmed that integrated use of comprehensive gene panel testing with orthogonal testing reduced the burden of inconclusive results.
KW - gene panel
KW - genetic diagnostics
KW - genetic testing
KW - osteochondrodysplasias
KW - skeletal disorders
KW - skeletal dysplasia
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U2 - 10.1002/ajmg.a.63646
DO - 10.1002/ajmg.a.63646
M3 - Article
C2 - 38702915
AN - SCOPUS:85192207925
SN - 1552-4825
VL - 194
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 9
M1 - e63646
ER -