Related Experiment Video
Updated: Feb 25, 2026
A Strategy to Identify de Novo Mutations in Common Disorders such as Autism and Schizophrenia
Published on: June 15, 2011
PLS3 sequencing in childhood-onset primary osteoporosis identifies two novel disease-causing variants
A J Kämpe1,2, A Costantini3,4, R E Mäkitie5
1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. anders.kampe@ki.se.
Insights
Genetic screening of PLS3 variants is crucial for diagnosing childhood-onset primary osteoporosis. Novel disease-causing variants were identified in two children with severe bone fragility, indicating PLS3
Area of Science:
- Genetics and Molecular Biology
- Pediatric Endocrinology
- Skeletal Dysplasias
Background:
- Primary bone fragility in children can lead to significant morbidity.
- X-linked osteoporosis is a rare genetic disorder caused by variants in the PLS3 gene.
- Identifying the genetic basis of bone fragility is essential for accurate diagnosis and management.
Purpose of the Study:
- To investigate the role of pathogenic PLS3 variants in pediatric bone fragility.
- To identify novel PLS3 variants and characterize their associated clinical phenotypes.
- To determine the diagnostic utility of PLS3 gene screening in children with primary osteoporosis.
Main Methods:
- Screening of 95 children with primary bone fragility for variants in the PLS3 gene.
- Two cohorts were analyzed: 31 with childhood-onset primary osteoporosis and 64 with multiple fractures.
- Sanger sequencing of PLS3 coding exons and flanking intronic regions was performed.
Main Results:
- Two novel, disease-causing PLS3 variants were identified in two unrelated children with severe osteoporosis and fractures.
- One patient was a male with a nonsense variant; the other was a female with a de novo missense variant.
- No pathogenic PLS3 variants were found in children with milder skeletal fragility or multiple fractures without primary osteoporosis.
Conclusions:
- Novel pathogenic PLS3 variants are associated with severe childhood-onset primary osteoporosis.
- PLS3 gene screening is indicated for male and female patients presenting with childhood-onset primary osteoporosis.
- These findings highlight the importance of PLS3 in pediatric bone health and disease.
Abstract:
Altogether 95 children with primary bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Two children with multiple peripheral and spinal fractures and low BMD had novel disease-causing PLS3 variants. Children with milder phenotypes had no pathogenic variants. PLS3 screening is indicated in childhood-onset primary osteoporosis.
Introduction:
The study aimed to determine the role of pathogenic PLS3 variants in children's bone fragility and to elucidate the associated phenotypic features.
Methods:
Two cohorts of children with bone fragility were screened for variants in PLS3, the gene underlying X-linked osteoporosis. Cohort I comprised 31 patients with childhood-onset primary osteoporosis of unknown etiology. Cohort II comprised 64 children who had sustained multiple fractures but were otherwise healthy. Clinical and radiological data were reviewed. Peripheral blood DNA was Sanger sequenced for coding exons and flanking intronic regions of PLS3.
Results:
In two patients of cohort I, where other common genetic causes had been excluded, we identified two novel disease-causing PLS3 variants. Patient 1 was a male with bilateral femoral fractures at 10 years, low BMD (Z-score -4.1; 18 years), and multiple vertebral compression fractures. He had a novel nonsense variant in PLS3. Patient 2 was a girl with multiple long bone and vertebral fractures and low BMD (Z-score -6.6 at 6 years). She had a de novo missense variant in PLS3; whole exome sequencing and array-CGH identified no other genetic causes. Iliac crest bone biopsies confirmed low-turnover osteoporosis in both patients. In cohort II, no pathogenic PLS3 variants were identified in any of the subjects.
Conclusions:
Two novel disease-causing variants in PLS3 were identified in a boy and a girl with multiple peripheral and spinal fractures and very low BMD while no pathogenic variants were identified in children with less severe skeletal fragility. PLS3 screening is warranted in male and female patients with childhood-onset primary osteoporosis.
Related Concept Videos
01:29Bone Disorders
Bone deposition is also affected by the levels of sex hormones like estrogen and testosterone that promote osteoblast activity and bone matrix synthesis. When the level of these hormones decreases due to aging, it causes a reduction in bone deposition. As a result, bone resorption by osteoclasts...
03:00Next-generation Sequencing
Next-Generation Sequencing Methods
Although all next-generation methods use different technologies, they all share a set of standard features....
01:31Osteoclasts in Bone Remodeling