Skeletal dysplasia is a group of disorders characterized by abnormal formation of the skeleton because of intrinsic derangement of growth, development, and/or differentiation. According to the latest International Classification of Skeletal Dysplasia, 42 subgroups with 461 disease entities have been established in this category. More than 90% of skeletal dysplasias are heritable (monogenic) diseases. The incidence of each disease is low, but as a whole, skeletal dysplasias affect about 1 in 1000 of the global population. Studies on skeletal dysplasia not only have important clinical significance (e.g., prenatal diagnosis, targeted therapy, prevention at the second pregnancy), but also provide the highest level of evidence for the mechanism of development and maintenance of the human skeleton by revealing the phenotypes of gene-knockout humans.
In the past decade, the etiology and classification of skeletal dysplasia have been improved significantly with advances in sequencing technology. The causal genes of the majority of the known skeletal dysplasias have been identified by whole exome/genome sequencing (WES/WGS). Though we now understand the genetic basis of more than 90% of skeletal dysplasia, the pathologic variants of the remaining “unsolved” skeletal dysplasias would be complex in structure or hidden in deep introns and intergenic regions, resulting in dramatically increased difficulty to find them compared to common variants within or around exons. Although WGS can be performed more easily than ever before, the analytic methods of WGS data remain immature. The abundance of information from a WGS dataset makes it difficult to identify the true variants. The problem is not limited to the field of skeletal dysplasia but exists in almost all fields of monogenic diseases. Furthermore, the effects of the identified variants need to be certified further by in vitro or in vivo functional experiments involving catalytic reactions, cellular physiology, developmental events, etc.
Skeletal dysplasias show high heterogeneity in phenotypes and genotypes. The same or similar phenotypes can be caused by different genes and mutations. The disease with the same causal gene often presents with diverse phenotypes, forming a continuous or non-continuous spectrum. Deciphering the complex genotype-phenotype association plays a key role in understanding the pathogenesis of the diseases and exploring the function of the causal genes in bone development and mechanisms.
This Research Topic welcomes any findings on genotype-phenotype studies in skeletal dysplasia referring to clinical reports, human genetics, and functional analysis of disease genes and variants using cells and model animals.
Integrative topics comprise, but are not limited to:
• Identification of genetic variation related to skeletal dysplasias in humans and other species. The findings of novel disease genes are particularly welcome. A single Case Report of novel disease genes will be considered if the effect of the variants is verified well.
• Clinical Case Report of skeletal dysplasias. The report of a case series with novel or recurrent mutations in known genes is welcome as long as it reveals new genotype-phenotype association.
• Methodology to identify genetic variants. The advancement of analytical or conceptual tools in solving the current problems is emphasized.
• Therapies for skeletal dysplasias.
• Functional analysis of the causal genes and variants for skeletal phenotypes.
• Studies of animal models (mouse, zebrafish, etc.) that help explain the genetic basis of skeletal dysplasias.
• Developmental biology, as it relates to skeletal phenotypes.
• Biology of chondrocytes, osteoblasts, and osteoclasts.
• Hypothesis of the genetics model and the pathogenesis of skeletal dysplasias.
• Reviews on this topic
Skeletal dysplasia is a group of disorders characterized by abnormal formation of the skeleton because of intrinsic derangement of growth, development, and/or differentiation. According to the latest International Classification of Skeletal Dysplasia, 42 subgroups with 461 disease entities have been established in this category. More than 90% of skeletal dysplasias are heritable (monogenic) diseases. The incidence of each disease is low, but as a whole, skeletal dysplasias affect about 1 in 1000 of the global population. Studies on skeletal dysplasia not only have important clinical significance (e.g., prenatal diagnosis, targeted therapy, prevention at the second pregnancy), but also provide the highest level of evidence for the mechanism of development and maintenance of the human skeleton by revealing the phenotypes of gene-knockout humans.
In the past decade, the etiology and classification of skeletal dysplasia have been improved significantly with advances in sequencing technology. The causal genes of the majority of the known skeletal dysplasias have been identified by whole exome/genome sequencing (WES/WGS). Though we now understand the genetic basis of more than 90% of skeletal dysplasia, the pathologic variants of the remaining “unsolved” skeletal dysplasias would be complex in structure or hidden in deep introns and intergenic regions, resulting in dramatically increased difficulty to find them compared to common variants within or around exons. Although WGS can be performed more easily than ever before, the analytic methods of WGS data remain immature. The abundance of information from a WGS dataset makes it difficult to identify the true variants. The problem is not limited to the field of skeletal dysplasia but exists in almost all fields of monogenic diseases. Furthermore, the effects of the identified variants need to be certified further by in vitro or in vivo functional experiments involving catalytic reactions, cellular physiology, developmental events, etc.
Skeletal dysplasias show high heterogeneity in phenotypes and genotypes. The same or similar phenotypes can be caused by different genes and mutations. The disease with the same causal gene often presents with diverse phenotypes, forming a continuous or non-continuous spectrum. Deciphering the complex genotype-phenotype association plays a key role in understanding the pathogenesis of the diseases and exploring the function of the causal genes in bone development and mechanisms.
This Research Topic welcomes any findings on genotype-phenotype studies in skeletal dysplasia referring to clinical reports, human genetics, and functional analysis of disease genes and variants using cells and model animals.
Integrative topics comprise, but are not limited to:
• Identification of genetic variation related to skeletal dysplasias in humans and other species. The findings of novel disease genes are particularly welcome. A single Case Report of novel disease genes will be considered if the effect of the variants is verified well.
• Clinical Case Report of skeletal dysplasias. The report of a case series with novel or recurrent mutations in known genes is welcome as long as it reveals new genotype-phenotype association.
• Methodology to identify genetic variants. The advancement of analytical or conceptual tools in solving the current problems is emphasized.
• Therapies for skeletal dysplasias.
• Functional analysis of the causal genes and variants for skeletal phenotypes.
• Studies of animal models (mouse, zebrafish, etc.) that help explain the genetic basis of skeletal dysplasias.
• Developmental biology, as it relates to skeletal phenotypes.
• Biology of chondrocytes, osteoblasts, and osteoclasts.
• Hypothesis of the genetics model and the pathogenesis of skeletal dysplasias.
• Reviews on this topic