Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature
Abstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS...
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doaj-5e01a665786b47638a7fcc09fc02b5f42021-07-04T11:32:51ZengBMCOrphanet Journal of Rare Diseases1750-11722021-07-0116111910.1186/s13023-021-01937-8Clinical relevance of targeted exome sequencing in patients with rare syndromic short statureGilyazetdinov Kamil0Ju Young Yoon1Sukdong Yoo2Chong Kun Cheon3Department of Pediatrics, National Children’s Medical CenterDivision of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children’s HospitalDivision of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children’s HospitalDivision of Pediatric Endocrinology, Department of Pediatrics, Pusan National University Children’s HospitalAbstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). Methods Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES. Results For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). Conclusions A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea.https://doi.org/10.1186/s13023-021-01937-8MutationShort statureSyndromeTargeted exome sequencing |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Gilyazetdinov Kamil Ju Young Yoon Sukdong Yoo Chong Kun Cheon |
spellingShingle |
Gilyazetdinov Kamil Ju Young Yoon Sukdong Yoo Chong Kun Cheon Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature Orphanet Journal of Rare Diseases Mutation Short stature Syndrome Targeted exome sequencing |
author_facet |
Gilyazetdinov Kamil Ju Young Yoon Sukdong Yoo Chong Kun Cheon |
author_sort |
Gilyazetdinov Kamil |
title |
Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
title_short |
Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
title_full |
Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
title_fullStr |
Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
title_full_unstemmed |
Clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
title_sort |
clinical relevance of targeted exome sequencing in patients with rare syndromic short stature |
publisher |
BMC |
series |
Orphanet Journal of Rare Diseases |
issn |
1750-1172 |
publishDate |
2021-07-01 |
description |
Abstract Background Large-scale genomic analyses have provided insight into the genetic complexity of short stature (SS); however, only a portion of genetic causes have been identified. In this study, we identified disease-causing mutations in a cohort of Korean patients with suspected syndromic SS by targeted exome sequencing (TES). Methods Thirty-four patients in South Korea with suspected syndromic disorders based on abnormal growth and dysmorphic facial features, developmental delay, or accompanying anomalies were enrolled in 2018–2020 and evaluated by TES. Results For 17 of 34 patients with suspected syndromic SS, a genetic diagnosis was obtained by TES. The mean SDS values for height, IGF-1, and IGFBP-3 for these 17 patients were − 3.27 ± 1.25, − 0.42 ± 1.15, and 0.36 ± 1.31, respectively. Most patients displayed distinct facial features (16/17) and developmental delay or intellectual disability (12/17). In 17 patients, 19 genetic variants were identified, including 13 novel heterozygous variants, associated with 15 different genetic diseases, including many inherited rare skeletal disorders and connective tissue diseases (e.g., cleidocranial dysplasia, Hajdu–Cheney syndrome, Sheldon–Hall, acromesomelic dysplasia Maroteaux type, and microcephalic osteodysplastic primordial dwarfism type II). After re-classification by clinical reassessment, including family member testing and segregation studies, 42.1% of variants were pathogenic, 42.1% were likely pathogenic variant, and 15.7% were variants of uncertain significance. Ultra-rare diseases accounted for 12 out of 15 genetic diseases (80%). Conclusions A high positive result from genetic testing suggests that TES may be an effective diagnostic approach for patients with syndromic SS, with implications for genetic counseling. These results expand the mutation spectrum for rare genetic diseases related to SS in Korea. |
topic |
Mutation Short stature Syndrome Targeted exome sequencing |
url |
https://doi.org/10.1186/s13023-021-01937-8 |
work_keys_str_mv |
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