Nosology and classification of genetic skeletal disorders: 2019 revision

Abstract

The application of massively parallel sequencing technology to the field of skeletal disorders has boosted the discovery of the underlying genetic defect for many of these diseases. It has also resulted in the delineation of new clinical entities and the identification of genes and pathways that had not previously been associated with skeletal disorders. These rapid advances have prompted the Nosology Committee of the International Skeletal Dysplasia Society to revise and update the last (2015) version of the Nosology and Classification of Genetic Skeletal Disorders. This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes.Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology.

Osteocyte Transcriptome Mapping Identifies a Molecular Landscape Controlling Skeletal Homeostasis and Susceptibility to Skeletal Disease

“…The majority of these genes have not previously been shown to have a role in bone, including genes that resulted in abnormal structural and functional skeletal phenotypes when deleted in mice. Integrating this map with orthogonal gene expression datasets 13,15,16,29,51 , functional skeletal phenotyping data 67 , GWAS datasets 26,65 , and the nosology of skeletal dysplasias 22 , provided new understanding of the fundamental role of the osteocyte in skeletal health and disease.…”

“…Given their functional role in mice, we next hypothesised that the osteocyte transcriptome signature would be enriched for genes that cause rare monogenic skeletal dysplasias in humans. Three-hundred and ninety two of 432 skeletal dysplasia-causing gene-orthologs 22 (~91%) were actively expressed in osteocytes supporting a key role for osteocytes in skeletal disease. Mutations in 90 genes present in the osteocyte transcriptome signature cause 168 of the 612 skeletal disorders annotated in the nosology of genetic skeletal disorders 22 (2.6-FE, p=6x10 -17 , Fig.…”

Two novel mutations of COL1A1 in fetal genetic skeletal dysplasia of Chinese

“…Congenital skeletal dysplasia, a complex group of diseases, is characterized by abnormal growth or morphology of the skeleton. According to 2019 edition of the Nosology (Mortier et al, 2019), 461 disorders classified within 42 different groups have been described based on radiologic, molecular and biochemical criteria. Currently accepted prevalence has been reported to be 2.3~7.6 per 10,000 births (Barbosa-Buck et al, 2012;Dighe, Fligner, Cheng, Warren, & Dubinsky, 2008;Rasmussen et al, 1996;Schramm & Mommsen, 2018;Stoll, Dott, Roth, & Alembik, 1989).…”

The Connective Tissue Disorder Associated with Recessive Variants in the SLC39A13 Zinc Transporter Gene (Spondylo-Dysplastic Ehlers–Danlos Syndrome Type 3): Insights from Four Novel Patients and Follow-Up on Two Original Cases

“…Later, the EDS nosology has used the name "spondylodysplastic EDS" for a group of three conditions, B3GALT6 deficiency (better known as spondyloepimetaphyseal dysplasia with joint laxity, Beighton type), B4GALT7 deficiency, and SLC39A13 deficiency (the original spondylo-cheiro-dysplastic type) [3]. Of note, these three conditions are also included in the 2019 revision of the skeletal dysplasia nosology [6]. SLC39A13 deficiency is rare and following the initial eight affected individuals, only a single case report has been published [7].…”